Rsv antiviral pyrazolo- and triazolo-pyrimidine compounds

ABSTRACT

The invention concerns novel substituted pyrazolo- and triazolo-pyrimidine compounds of formula (I) having antiviral activity, in particular, having an inhibitory activity on the replication of the respiratory syncytial virus (RSV). The invention further concerns pharmaceutical compositions comprising these compounds and the compounds for use in the treatment of respiratory syncytial virus infection.

FIELD OF THE INVENTION

The invention concerns novel substituted pyrazolo- andtriazolo-pyrimidine compounds having antiviral activity, in particular,having an inhibitory activity on the replication of the respiratorysyncytial virus (RSV). The invention further concerns pharmaceuticalcompositions comprising these compounds and the compounds for use in thetreatment of respiratory syncytial virus infection.

BACKGROUND

Human RSV or Respiratory Syncytial Virus is a large RNA virus, member ofthe family of Paramyxoviridae, subfamily pneumoviridae together withbovine RSV virus. Human RSV is responsible for a spectrum of respiratorytract diseases in people of all ages throughout the world. It is themajor cause of lower respiratory tract illness during infancy andchildhood. Over half of all infants encounter RSV in their first year oflife, and almost all within their first two years. The infection inyoung children can cause lung damage that persists for years and maycontribute to chronic lung disease in later life (chronic wheezing,asthma). Older children and adults often suffer from a (bad) common coldupon RSV infection. In old age, susceptibility again increases, and RSVhas been implicated in a number of outbreaks of pneumonia in the agedresulting in significant mortality.

Infection with a virus from a given subgroup does not protect against asubsequent infection with an RSV isolate from the same subgroup in thefollowing winter season. Re-infection with RSV is thus common, despitethe existence of only two subtypes, A and B.

Today only three drugs have been approved for use against RSV infection.A first one is ribavirin, a nucleoside analogue that provides an aerosoltreatment for serious RSV infection in hospitalized children. Theaerosol route of administration, the toxicity (risk of teratogenicity),the cost and the highly variable efficacy limit its use. The other twodrugs, RespiGam® (RSV-IG) and Synagis® (palivizumab), polyclonal andmonoclonal antibody immunostimulants, are intended to be used in apreventive way. Both are very expensive, and require parenteraladministration.

Clearly there is a need for an efficacious non-toxic and easy toadminister drug against RSV replication. It would be particularlypreferred to provide drugs against RSV replication that could beadministered perorally.

Compounds that exhibit anti-RSV activity are disclosed inWO-2005/042530.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of formula (I)

including any stereochemically isomeric form thereof, wherein

-   X is N or CR⁶ wherein R⁶ is hydrogen, halo or C₁₋₄alkyl;-   R¹ is CH₃ or CH₂CH₃, and R^(1′) is hydrogen; or R¹ and R^(1′) are    taken together with the carbon atom to which they are attached to    form cyclopropyl; and R² is C₃₋₆alkyl and R³ is C₁₋₄alkyl; or the

moiety is a radical of formula:

wherein R¹ is CH₃ or CH₂CH₃, and R¹ is hydrogen; or R¹ is absent inradical (a-6); or R¹ and R¹ are taken together with the carbon atom towhich they are attached to form cyclopropyl; and radical (a-1) to (a-30)are optionally substituted with one or two substituents eachindependently selected from C₁₋₂alkyl and halo;

-   R⁴ is C₁₋₆alkyl; C₃₋₆alkenyl, polyhaloC₁₋₄alkyl; C₁₋₄alkyl    substituted with one C₃₋₆cycloalkyl; aminocarbonyl, mono- or    di(C₁₋₄alkyl)aminocarbonyl; oxetanyl optionally substituted with    C₁₋₄alkyl; Heteroaryl¹; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl substituted    with one or two substituents each individually selected from    hydroxy, halo, cyano, C₁₋₄alkyl, C₁₋₄alkyloxy, polyhaloC₁₋₄alkyl,    and polyhaloC₁₋₄alkyloxy; or    -   NR⁷R⁸ whereinR⁷ is selected from hydrogen and C₁₋₄alkyl;        -   R⁸ is C₁₋₄alkyl or C₃₋₆cycloalkyl;    -   or R⁷ and R⁸ are taken together with the nitrogen to which they        are attached to form azetidinyl, pyrrolidinyl or piperidinyl;-   R⁵ is C₃₋₆cycloalkyl;    -   Heteroaryl;    -   Bicycle;

naphthyl substituted with 1, 2 or 3 substituents each independentlyselected from halo and hydroxycarbonyl;

-   -   phenyl substituted with 1, 2 or 3 substituents each        independently selected from hydroxy;        -   halo;        -   C₁₋₆alkyl;        -   C₁₋₆alkyl substituted with one, two or three substituents            each independently selected from halo, hydroxy,            hydroxycarbonyl, aminocarbonyl,            -   Heterocycle, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl substituted                with one or two substituents each independently selected                from C₁₋₄alkyl, halo, hydroxycarbonyl, and C₁₋₄alkyl                substituted with hydroxycarbonyl;        -   C₃₋₆alkenyl;        -   C₃₋₆alkenyl substituted with one or two substituents            selected from C₁₋₆alkyl, hydroxy, hydroxycarbonyl and            aminocarbonyl;        -   C₃₋₆alkynyl;        -   C₃₋₆alkynyl substituted with one hydroxycarbonyl;        -   C₃₋₆cycloalkyl;        -   C₃₋₆cycloalkyl substituted with one, two or three            substituents each independently selected from C₁₋₄alkyl,            halo, hydroxycarbonyl, and C₁₋₄alkyl substituted with            hydroxycarbonyl;        -   C₃₋₆cycloalkenyl;        -   C₃₋₆cycloalkenyl substituted with one hydroxycarbonyl;        -   C₁₋₆alkyloxy optionally substituted with hydroxycarbonyl;        -   polyhaloC₁₋₄alkyl;        -   polyhaloC₁₋₄alkyloxy;        -   cyano;        -   nitro;        -   B(OH)₂;        -   hydroxycarbonyl;        -   CO—NHOH;        -   CO—NR⁹R¹⁰;        -   CO—NH—NR⁹R¹⁰;        -   NR⁹ _(R) ¹⁰;        -   NH—CO—R¹¹;        -   NH—CO—O—R¹¹;        -   NH—CO—NH—R¹¹;        -   NH—CS—NH—R¹¹;        -   NH—C═(N—CN)—NH—R¹¹;

-   aminosulfonyl; mono- or di(C₁₋₄alkyl)aminosulfonyl;

-   Heterocycle; and

-   spiro[3.3]heptanyl optionally substituted with hydroxycarbonyl;

-   wherein

-   R⁹ and R¹⁰ are each independently selected from hydrogen; C₁₋₆alkyl;    SO₂—R¹²; and    -   C₁₋₆alkyl substituted with one or two substituents each        independently selected from hydroxy, hydroxycarbonyl,        C₃₋₆cycloalkyl, C₃₋₆cycloalkyl substituted with hydroxycarbonyl,        C₁₋₄alkylcarbonylamino, mono- or di(C₁₋₄alkyl)amino, and        Heterocycle;

-   R¹¹ is C₁₋₆alkyl; C₃₋₆alkenyl; C₃₋₆cycloalkyl; Aryl; Heterocycle; or    C₁₋₆alkyl substituted with one substituent selected from    C₃₋₆cycloalkyl, C₁₋₄alkyloxy, hydroxy, cyano, hydroxycarbonyl,    aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl,    C₁₋₄alkylcarbonylamino, and Heterocycle;

-   R¹² is C₁₋₄alkyl, C₃₋₆cycloalkyl, or C₁₋₄alkyl substituted with one    C₃₋₆cycloalkyl, Heteroaryl is thienyl, imidazolyl, pyrazolyl,    thiazolyl, pyridinyl, 1-benzopyrazolyl, 2,3-dihydro-1H-indolyl,    2-oxo-2,3-dihydro-1H-indolyl, quinolinyl, 2-oxo-quinolinyl,    benzimidazolyl, cinnolinyl, or 2H-chromenyl, wherein each Heteroaryl    is optionally substituted with one or two substituents each    independently selected from C₁₋₄alkyl, halo, amino, aminocarbonyl,    and NH—CO—C₃₋₆cycloalkyl;

-   Heteroaryl¹ is imidazolyl or pyrazolyl; wherein each Heteroaryl¹ is    optionally substituted with one or two substituents each    independently selected from C₁₋₄alkyl, halo and hydroxycarbonyl;

-   Heterocycle is azetidinyl, tetrahydrofuranyl, pyrrolidinyl, furanyl,    thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl,    1,2,4-oxadiazolyl, 2,5-dihydro-1H-pyrrolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 2-oxo-azepanyl, 2,5-dioxopyrrolidinyl, or    3-oxo-2,3-dihydro-1,2-oxazolyl; wherein each Heterocycle is    optionally substituted with one or two substituents each    independently selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, halo,    hydroxyC₁₋₄alkyl, polyhaloC₁₋₄alkyl, hydroxycarbonyl, and C₁₋₄alkyl    substituted with hydroxycarbonyl;

-   Aryl is phenyl substituted with one or two substituents each    independently selected from hydrogen, halogen, C₁₋₄alkyl,    C₁₋₄alkyloxy, and trifluoromethyl;

-   Bicycle is 1,2,3,4-tetrahydronaphthalenyl, chromanyl or    2,3-dihydrobenzofuranyl;    -   wherein each Bicycle is optionally substituted with one or two        substituents each independently selected from C₁₋₄alkyl, halo        and hydroxycarbonyl;

-   with the proviso that    [7-ethyl-2-(3-thienyl)pyrazolo[1,5-a]pyrimidin-5-yl](2-methyl-1-piperidinyl)-methanone    and    [7-ethyl-2-(2-pyridinyl)pyrazolo[1,5-a]pyrimidin-5-yl](2-methyl-1-piperidinyl)-methanone    are not included;

-   or a pharmaceutically acceptable acid addition salt thereof.

As used in the foregoing definitions:

-   halo is generic to fluoro, chloro, bromo and iodo;-   C₁₋₂alkyl defines saturated hydrocarbon radicals having from 1 to 2    carbon atoms such as methyl and ethyl;-   C₁₋₄alkyl defines straight and branched chain saturated hydrocarbon    radicals having from 1 to 4 carbon atoms such as, for example,    methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the    like;-   C₁₋₆alkyl is meant to include C₁₋₄alkyl and the higher homologues    thereof having 5 or 6 carbon atoms, such as, for example, 2    methylbutyl, pentyl, hexyl and the like;-   C₃₋₆alkenyl defines straight and branched chain unsaturated    hydrocarbon radicals having from 3 to 6 carbon atoms, such as    propenyl, butenyl, pentenyl or hexenyl;-   C₃₋₆alkynyl defines straight and branched chain unsaturated    hydrocarbon radicals having from 3 to 6 carbon atoms, such as    propynyl, butynyl, pentynyl or hexynyl;-   C₃₋₆cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl,    and cyclohexyl;-   C₃₋₆cycloalkenyl is generic to cyclopropenyl, cyclobutenyl,    cyclopentenyl, and cyclohexenyl;-   polyhaloC₁₋₄alkyl is defined as polyhalosubstituted C₁₋₄alkyl, in    particular C₁₋₄alkyl (as hereinabove defined) substituted with 2 to    6 halogen atoms such as difluoromethyl, trifluoromethyl,    trifluoroethyl, and the like.

The term “compounds of the invention” as used herein, is meant toinclude the compounds of formula (I), and the salts and solvatesthereof.

As used herein, any chemical formula with bonds shown only as solidlines and not as solid wedged or hashed wedged bonds, or otherwiseindicated as having a particular configuration (e.g. R, S) around one ormore atoms, contemplates each possible stereoisomer, or mixture of twoor more stereoisomers.

Hereinbefore and hereinafter, the terms “compound of formula (I)” and“intermediates of synthesis of formula (I)” are meant to include thestereoisomers thereof and the tautomeric forms thereof

The terms “stereoisomers”, “stereoisomeric forms” or “stereochemicallyisomeric forms” hereinbefore or hereinafter are used interchangeably.

The invention includes all stereoisomers of the compounds of theinvention either as a pure stereoisomer or as a mixture of two or morestereoisomers. Enantiomers are stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is aracemate or racemic mixture. Diastereomers (or diastereoisomers) arestereoisomers that are not enantiomers, i.e. they are not related asmirror images. If a compound contains a double bond, the substituentsmay be in the E or the Z configuration. Substituents on bivalent cyclic(partially) saturated radicals may have either the cis- ortrans-configuration; for example if a compound contains a disubstitutedcycloalkyl group, the substituents may be in the cis or transconfiguration.

The term “stereoisomers” also includes any rotamers, also calledconformational isomers, the compounds of formula (I) may form.

Therefore, the invention includes enantiomers, diastereomers, racemates,E isomers, Z isomers, cis isomers, trans isomers, rotamers, and mixturesthereof, whenever chemically possible.

The meaning of all those terms, i.e. enantiomers, diastereomers,racemates, E isomers, Z isomers, cis isomers, trans isomers and mixturesthereof are known to the skilled person.

The absolute configuration is specified according to theCahn-Ingold-Prelog system. The configuration at an asymmetric atom isspecified by either R or S. Resolved stereoisomers whose absoluteconfiguration is not known can be designated by (+) or ( )depending onthe direction in which they rotate plane polarized light. For instance,resolved enantiomers whose absolute configuration is not known can bedesignated by (+) or (−) depending on the direction in which they rotateplane polarized light.

When a specific stereoisomer is identified, this means that saidstereoisomer is substantially free, i.e. associated with less than 50%,preferably less than 20%, more preferably less than 10%, even morepreferably less than 5%, in particular less than 2% and most preferablyless than 1%, of the other stereoisomers. Thus, when a compound offormula (I) is for instance specified as (R), this means that thecompound is substantially free of the (S) isomer; when a compound offormula (I) is for instance specified as E, this means that the compoundis substantially free of the Z isomer; when a compound of formula (I) isfor instance specified as cis, this means that the compound issubstantially free of the trans isomer.

Some of the compounds according to formula (I) may also exist in theirtautomeric form. Such forms in so far as they may exist, although notexplicitly indicated in the above formula (I) are intended to beincluded within the scope of the present invention.

It follows that a single compound may exist in both stereoisomeric andtautomeric form.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms that the compounds of formula (I) are able toform. These pharmaceutically acceptable acid addition salts canconveniently be obtained by treating the base form with such appropriateacid. Appropriate acids comprise, for example, inorganic acids such ashydrohalic acids, e.g.

hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and thelike acids; or organic acids such as, for example, acetic, propanoic,hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic,succinic (i.e. butane-dioic acid), maleic, fumaric, malic, tartaric,citric, methanesulfonic, ethanesulfonic, benzenesulfonic, ptoluenesulfonic, cyclamic, salicylic, p aminosalicylic, pamoic and thelike acids.

Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The compounds of formula (I) may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecularassociation comprising a compound of the invention and one or morepharmaceutically acceptable solvent molecules, e.g. water or ethanol.The term ‘hydrate’ is used when said solvent is water.

For the avoidance of doubt, compounds of formula (I) may contain thestated atoms in any of their natural or non-natural isotopic forms. Inthis respect, embodiments of the invention that may be mentioned includethose in which (a) the compound of formula (I) is not isotopicallyenriched or labelled with respect to any atoms of the compound; and (b)the compound of formula (I) is isotopically enriched or labelled withrespect to one or more atoms of the compound. Compounds of formula (I)that are isotopically enriched or labelled (with respect to one or moreatoms of the compound) with one or more stable isotopes include, forexample, compounds of formula (I) that are isotopically enriched orlabelled with one or more atoms such as deuterium, 13C_(,) 14C_(,)14N_(,) 150 or the like. Particular compounds of formula (I) that areisotopically enriched are the compounds of formula (I) wherein R⁶ isdeuterium.

In a first embodiment the invention concerns compounds of formula (I),including any stereochemically isomeric forms thereof,

-   wherein R¹ is CH₃ or CH₂CH₃, and R^(1′) is hydrogen; or R^(1′) is    absent in radical (a-6); or R¹ and R^(1′) are taken together with    the carbon atom to which they are attached to form cyclopropyl; and    radical (a-1) to (a-15) are optionally substituted with one or two    substituents each independently selected from C₁₋₂alkyl and halo;-   R⁴ is C₁₋₆alkyl; polyhaloC₁₋₄alkyl; C₁₋₄alkyl substituted with one    C₃₋₆cycloalkyl; or    -   NR⁷R⁸ wherein R⁷ is selected from hydrogen and C₁₋₄alkyl;        -   -   R⁸ is C₁₋₄alkyl or C₃₋₆cycloalkyl;    -   or R⁷ and R⁸ are taken together with the nitrogen to which they        are attached to form azetidinyl, pyrrolidinyl or piperidinyl;-   R⁵ is C₃₋₆cycloalkyl;    -   Heteroaryl;    -   naphthyl substituted with 1, 2 or 3 substituents each        independently selected from halo and hydroxycarbonyl;    -   phenyl substituted with 1, 2 or 3 substituents each        independently selected from hydroxy;        -   halo;        -   C₁₋₆alkyl;        -   C₁₋₆alkyl substituted with one substituent selected from            hydroxy, hydroxycarbonyl and aminocarbonyl;        -   C₃₋₆alkenyl;        -   C₃₋₆alkenyl substituted with one or two substituents            selected from        -   C₁₋₆alkyl, hydroxy, hydroxycarbonyl and aminocarbonyl;        -   C₃₋₆alkynyl;        -   C₃₋₆alkynyl substituted with one hydroxycarbonyl;        -   C₃₋₆cycloalkyl;        -   C₃₋₆cycloalkyl substituted with one hydroxycarbonyl;        -   C₃₋₆cycloalkenyl;        -   C₃₋₆cycloalkenyl substituted with one hydroxycarbonyl;        -   C ₁₋₆alkyloxy;        -   polyhaloC₁₋₄alkyl;        -   cyano;        -   nitro;        -   B(OH)₂;        -   hydroxycarbonyl;        -   CO—NHOH;        -   CO—NR⁹R¹⁰;        -   CO—NH—NR⁹R¹⁰;        -   NR⁹R¹⁰;        -   NH—CO—R¹¹;        -   NH—CO—O—R¹¹;        -   NH—CO—NH—R¹¹;        -   NH—CS—NH—R¹¹;        -   NH—C═(N—CN)—NH—R¹¹;        -   aminosulfonyl; mono- or di(C₁₋₄alkyl)aminosulfonyl; and        -   Heterocycle;-   wherein-   R⁹ and R¹⁰ are each independently selected from hydrogen; C₁₋₆alkyl;    SO₂—R¹²; and C₁₋₆alkyl substituted with hydroxy, hydroxycarbonyl,    C₃₋₆cycloalkyl, C₁₋₄alkylcarbonylamino, mono- or di(C₁₋₄alkyl)amino,    or Heterocycle;-   R¹¹ is C₁₋₆alkyl; C₃₋₆alkenyl; C₃₋₆cycloalkyl; Aryl; Heterocycle; or    C₁₋₆alkyl substituted with one substituent selected from    C₃₋₆cycloalkyl, C₁₋₄alkyloxy, hydroxy, cyano, hydroxycarbonyl,    aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl,    C₁₋₄alkylcarbonylamino, and Heterocycle;-   R¹² is C₁₋₄alkyl, C₃₋₆cycloalkyl, or C₁₋₄alkyl substituted with one    C₃₋₆cycloalkyl,-   Heteroaryl is thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl,    1-benzopyrazolyl, 2,3-dihydro-1H-indolyl,    2-oxo-2,3-dihydro-1H-indolyl, quinolinyl, 2-oxo-quinolinyl,    benzimidazolyl, or cinnolinyl, wherein each Heteroaryl is optionally    substituted with one or two substituents each independently selected    from C₁₋₄alkyl, halo, amino, aminocarbonyl, and    NH—CO—C₃₋₆cycloalkyl;-   Heterocycle is tetrahydrofuranyl, pyrrolidinyl, furanyl, thienyl,    imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,    2-oxo-azepanyl, or 2,5-dioxopyrrolidinyl; wherein each Heterocycle    is optionally substituted with one or two substituents each    independently selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, halo and    hydroxycarbonyl;-   Aryl is phenyl substituted with one or two substituents each    independently selected from hydrogen, halogen, C₁₋₄alkyl,    C₁₋₄alkyloxy, and trifluoromethyl; with the proviso that    [7-ethyl-2-(3-thienyl)pyrazolo[1,5-a]pyrimidin-5-yl](2-methyl-1-piperidinyl)-methanone    and    [7-ethyl-2-(2-pyridinyl)pyrazolo[1,5-a]pyrimidin-5-yl](2-methyl-1-piperidinyl)-methanone    are not included;-   or a pharmaceutically acceptable acid addition salt thereof.

In a second embodiment the invention concerns compounds of formula (I),including any stereochemically isomeric forms thereof, wherein

-   X is N or CR⁶ wherein R⁶ is hydrogen or halo;-   R¹ is CH₃ or CH₂CH₃, and R^(1′) is hydrogen; or R¹ and R^(1′) are    taken together with the carbon atom to which they are attached to    form cyclopropyl; and R² is C₃₋₆alkyl and R³ is CH₃;-   or the

moiety is a radical of formula:

wherein R¹ is CH₃ or CH₂CH₃, and R^(1′) is hydrogen; or R^(1′) is absentin radical (a-6); or R¹ and R^(1′) are taken together with the carbonatom to which they are attached to form cyclopropyl; and radical (a-1)to (a-15) are optionally substituted with one or two substituents eachindependently selected from C₁₋₂alkyl and halo;

-   R⁴ is C₁₋₆alkyl; polyhaloC₁₋₄alkyl; C₃₋₆cycloalkyl; C₁₋₄alkyl    substituted with one C₃₋₆cycloalkyl; or    -   NR⁷R⁸ wherein R⁷ is selected from hydrogen and C₁₋₄alkyl;    -   R⁸ is C₁₋₄alkyl or C₃₋₆cycloalkyl;    -   or R⁷ and R⁸ are taken together with the nitrogen to which they        are attached to form pyrrolidinyl or piperidinyl;-   R⁵ is C₃₋₆cycloalkyl;    -   Heteroaryl;    -   phenyl substituted with 1, 2 or 3 substituents each        independently selected from        -   hydroxy;        -   halo;        -   C₁₋₆alkyl;        -   C₁₋₆alkyl substituted with one substituent selected from            hydroxy, hydroxycarbonyl and aminocarbonyl;        -   C₃₋₆alkenyl substituted with one or two substituents            selected from C₁₋₆alkyl, hydroxy, hydroxycarbonyl and            aminocarbonyl;        -   C₃₋₆cycloalkyl substituted with one hydroxycarbonyl;        -   C₁₋₆alkyloxy;        -   cyano;        -   B(OF)₂;        -   hydroxycarbonyl;        -   CO—NHOH;        -   CO—NR⁹R10;        -   CO—NH—NR⁹R¹⁰;        -   NR⁹R¹⁰;        -   NH—CO—R¹¹;        -   NH—CO—O—R¹¹;        -   NH—CO—NH—R¹¹;        -   NH—CS—NH—R¹¹;        -   NH—C═(N—CN)—NH—R¹¹;        -   aminosulfonyl; mono- or di(C₁₋₄alkyl)aminosulfonyl; and        -   Heterocycle;-   wherein-   R⁹ and R¹⁰ are each independently selected from hydrogen; C₁₋₆alkyl;    SO₂—R¹²; and C₁₋₆alkyl substituted with C₃₋₆cycloalkyl, mono- or    di(C₁₋₄alkyl)amino, or Heterocycle;-   R¹¹ is C₁₋₆alkyl; C₃₋₆alkenyl; C₃₋₆cycloalkyl; Aryl; Heterocycle; or    C₁₋₆alkyl substituted with one substituent selected from    C₃₋₆cycloalkyl, C₁₋₄alkyloxy, hydroxy, cyano, hydroxycarbonyl,    aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl,    C₁₋₄alkylcarbonylamino, and Heterocycle;-   R¹² is C₁₋₄alkyl, or C₃₋₆cycloalkyl;-   Heteroaryl is thienyl, pyridinyl, 1-benzopyrazolyl,    2,3-dihydro-1H-indolyl, 2-oxo-2,3-dihydro-1H-indolyl, quinolinyl,    2-oxo-quinolinyl, benzimidazolyl, cinnolinyl, or 2H-chromenyl;    -   wherein each Heteroaryl is optionally substituted with one or        two substituents each independently selected from C₁₋₄alkyl,        halo, aminocarbonyl, and NH—CO—C₃₋₆cycloalkyl;-   Heterocycle is azetidinyl, tetrahydrofuranyl, pyrrolidinyl, furanyl,    thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 2-oxo-azepanyl, 2,5-dioxopyrrolidinyl, or    3-oxo-2,3-dihydro-1,2-oxazolyl; wherein each Heterocycle is    optionally substituted with one or two substituents each    independently selected from C₃₋₆cycloalkyl, halo and    hydroxycarbonyl;-   Aryl is phenyl substituted with one or two substituents each    independently selected from hydrogen and halogen;-   with the proviso that    [7-ethyl-2-(3-thienyl)pyrazolo[1,5-a]pyrimidin-5-yl](2-methyl-1-piperidinyl)-methanone    and    [7-ethyl-2-(2-pyridinyl)pyrazolo[1,5-a]pyrimidin-5-yl](2-methyl-1-piperidinyl)-methanone    are not included;-   or a pharmaceutically acceptable acid addition salt thereof.

In a third embodiment the invention concerns compounds of formula (I),including any stereochemically isomeric forms thereof, wherein

-   X is N or CR⁶ wherein R⁶ is hydrogen, halo or C₁₋₄alkyl;-   R¹ is CH₃ or CH₂CH₃, and R^(1′) is hydrogen; or R¹ and R¹ are taken    together with the carbon atom to which they are attached to form    cyclopropyl; and R² is C₃₋₆alkyl and R³ is C₁₋₄alkyl;-   or the

moiety is a radical of formula:

wherein R¹ is CH₃ or CH₂CH₃, and R^(1′) is hydrogen; or R^(1′) is absentin radical (a-6);

-   or R¹ and R¹ are taken together with the carbon atom to which they    are attached to form cyclopropyl; and radical (a-1) to (a-15) are    optionally substituted with one or two substituents each    independently selected from C₁₋₂alkyl and halo;-   R⁴ is C₁₋₆alkyl; polyhaloC₁₋₄alkyl; C₃₋₆cycloalkyl; C₁₋₄alkyl    substituted with one C₃₋₆cycloalkyl; or    -   NR⁷R⁸ whereinR⁷ is selected from hydrogen and C₁₋₄alkyl;        -   R⁸ is C₁₋₄alkyl or C₃₋₆cycloalkyl;    -   or R⁷ and R⁸ are taken together with the nitrogen to which they        are attached to form azetidinyl, pyrrolidinyl or piperidinyl;-   R⁵ is C₃₋₆cycloalkyl;    -   Heteroaryl;    -   naphthyl substituted with 1, 2 or 3 substituents each        independently selected from halo and hydroxycarbonyl;    -   phenyl substituted with 1, 2 or 3 substituents each        independently selected from hydroxy;        -   halo;        -   C₁₋₆alkyl;        -   C₁₋₆alkyl substituted with one substituent selected from            hydroxy, hydroxycarbonyl and aminocarbonyl;        -   C₃₋₆alkenyl;        -   C₃₋₆alkenyl substituted with one or two substituents            selected from        -   C₁₋₆alkyl, hydroxy, hydroxycarbonyl and aminocarbonyl;        -   C₃₋₆alkynyl;        -   C₃₋₆alkynyl substituted with one hydroxycarbonyl;        -   C₃₋₆cycloalkyl;        -   C₃₋₆cycloalkyl substituted with one hydroxycarbonyl;        -   C₃₋₆cycloalkenyl;        -   C₃₋₆cycloalkenyl substituted with one hydroxycarbonyl;        -   C₁₋₆alkyloxy;        -   polyhaloC₁₋₄alkyl;        -   cyano;        -   nitro;        -   B(OH)₂;        -   hydroxycarbonyl;        -   CO—NHOH;        -   CO—NR⁹R¹⁰;        -   CO—NH—NR⁹R¹⁰;        -   NR⁹R¹⁰;        -   NH—CO—R¹¹;        -   NH—CO—O—R¹¹;        -   NH—CO—NH—R¹¹;        -   NH—CS—NH—R¹¹;        -   NH—C═(N—CN)—NH—R¹¹;        -   aminosulfonyl; mono- or di(C₁₋₄alkyl)aminosulfonyl; and        -   Heterocycle;-   wherein-   R⁹ and R¹⁰ are each independently selected from hydrogen; C₁₋₆alkyl;    SO₂—R¹²; and C₁₋₆alkyl substituted with hydroxy, hydroxycarbonyl,    C₃₋₆cycloalkyl, C₁₋₄alkylcarbonylamino, mono- or di(C₁₋₄alkyl)amino,    or Heterocycle;-   R11 is C₁₋₆alkyl; C₃₋₆alkenyl; C₃₋₆cycloalkyl; Aryl; Heterocycle; or    C₁₋₆alkyl substituted with one substituent selected from    C₃₋₆cycloalkyl, C₁₋₄alkyloxy, hydroxy, cyano, hydroxycarbonyl,    aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl,    C₁₋₄alkylcarbonylamino, and Heterocycle;-   R¹² is C₁₋₄alkyl, C₃₋₆cycloalkyl, or C₁₋₄alkyl substituted with one    C₃₋₆cycloalkyl,-   Heteroaryl is thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl,    1-benzopyrazolyl, 2,3-dihydro-1H-indolyl,    2-oxo-2,3-dihydro-1H-indolyl, quinolinyl, 2-oxo-quinolinyl,    benzimidazolyl, cinnolinyl, or 2H-chromenyl, wherein each Heteroaryl    is optionally substituted with one or two substituents each    independently selected from C₁₋₄alkyl, halo, amino, aminocarbonyl,    and NH—CO—C₃₋₆cycloalkyl;-   Heterocycle is azetidinyl, tetrahydrofuranyl, pyrrolidinyl, furanyl,    thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 2-oxo-azepanyl, 2,5-dioxopyrrolidinyl, or    3-oxo-2,3-dihydro-1,2-oxazolyl; wherein each Heterocycle is    optionally substituted with one or two substituents each    independently selected from C₃₋₆cycloalkyl, halo and    hydroxycarbonyl;-   Aryl is phenyl substituted with one or two substituents each    independently selected from hydrogen, halogen, C₁₋₄alkyl,    C₁₋₄alkyloxy, and trifluoromethyl;-   with the proviso that    [7-ethyl-2-(3-thienyl)pyrazolo[1,5-a]pyrimidin-5-yl](2-methyl-1-piperidinyl)-methanone    and    [7-ethyl-2-(2-pyridinyl)pyrazolo[1,5-a]pyrimidin-5-yl](2-methyl-1-piperidinyl)-methanone    are not included;-   or a pharmaceutically acceptable acid addition salt thereof.

A first group of compounds are compounds of formula (I-a)

including any stereochemically isomeric form thereof, wherein

-   R⁶ is hydrogen, halo or C₁₋₄alkyl;-   R¹ is CH₃ or CH₂CH₃, and Rl is hydrogen; or R¹ and R^(1′) are taken    together with the carbon atom to which they are attached to form    cyclopropyl; and R² is C₃₋₆alkyl and R³ is C₁₋₄alkyl;-   R⁴ is C₁₋₆alkyl; polyhaloC₁₋₄alkyl; C₃₋₆cycloalkyl; C₁₋₄alkyl    substituted with one C₃₋₆cycloalkyl; or NR⁷R⁸ wherein R⁷ is selected    from hydrogen and C₁₋₄alkyl; R⁸ is C₁₋₄alkyl or C₃₋₆cycloalkyl; or    R⁷ and R⁸ are taken together with the nitrogen to which they are    attached to form azetidinyl, pyrrolidinyl or piperidinyl;-   R⁵ is C₃₋₆cycloalkyl; Heteroaryl; naphthyl substituted with 1, 2 or    3 substituents each independently selected from halo and    hydroxycarbonyl; phenyl substituted with 1, 2 or 3 substituents each    independently selected from hydroxy; halo; C₁₋₆alkyl; C₁₋₆alkyl    substituted with one substituent selected from hydroxy,    hydroxycarbonyl and aminocarbonyl; C₃₋₆alkenyl; C₃₋₆alkenyl    substituted with one or two substituents selected from C₁₋₆alkyl,    hydroxy, hydroxycarbonyl and aminocarbonyl; C₃₋₆alkynyl; C₃₋₆alkynyl    substituted with one hydroxycarbonyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl    substituted with one hydroxycarbonyl; C₃₋₆cycloalkenyl;    C₃₋₆cycloalkenyl substituted with one hydroxycarbonyl; C₁₋₆alkyloxy;    polyhaloC₁₋₄alkyl; cyano; nitro; B(OH)₂; hydroxycarbonyl; CO—NHOH;    CO—NR⁹R¹⁰; CO—NH—NR⁹R¹⁰; NR⁹R¹⁰; NH—CO—R¹¹; NH—CO—O—R¹¹;    NH—CO—NH—R¹¹; NH—CS—NH—RH; NH—C═(N—CN)—NH—R¹¹; aminosulfonyl; mono-    or di(C₁₋₄alkyl)aminosulfonyl; and Heterocycle;-   wherein-   R⁹ and R¹⁰ are each independently selected from hydrogen; C₁₋₆alkyl;    SO₂—R¹²; and C₁₋₆alkyl substituted with hydroxy, hydroxycarbonyl,    C₃₋₆cycloalkyl, C₁₋₄alkylcarbonylamino, mono- or di(C₁₋₄alkyl)amino,    or Heterocycle;-   R¹¹ is C₁₋₆alkyl; C₃₋₆alkenyl; C₃₋₆cycloalkyl; Aryl; Heterocycle; or    C₁₋₆alkyl substituted with one substituent selected from    C₃₋₆cycloalkyl, C₁₋₄alkyloxy, hydroxy, cyano, hydroxycarbonyl,    aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl,    C₁₋₄alkylcarbonylamino, and Heterocycle;-   R¹² is C₃₋₆cycloalkyl, or C₁₋₄alkyl substituted with one    C₃₋₆cycloalkyl,-   Heteroaryl is thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl,    1-benzopyrazolyl, 2,3-dihydro-1H-indolyl,    2-oxo-2,3-dihydro-1H-indolyl, quinolinyl, 2-oxo-quinolinyl,    benzimidazolyl, cinnolinyl, or 2H-chromenyl, wherein each Heteroaryl    is optionally substituted with one or two substituents each    independently selected from C₁₋₄alkyl, halo, amino, aminocarbonyl,    and NH—CO—C₃₋₆cycloalkyl;-   Heterocycle is azetidinyl, tetrahydrofuranyl, pyrrolidinyl, furanyl,    thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 2-oxo-azepanyl, 2,5-dioxo-pyrrolidinyl or    3-oxo-2,3-dihydro-1,2-oxazolyl; wherein each Heterocycle is    optionally substituted with one or two substituents each    independently selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, halo and    hydroxycarbonyl;-   Aryl is phenyl substituted with one or two substituents each    independently selected from hydrogen, halogen, C₁₋₄alkyl,    C₁₋₄alkyloxy, and trifluoromethyl;-   or a pharmaceutically acceptable acid addition salt thereof.

A second group of compounds are compounds of formula (I-b)

including any stereochemically isomeric form thereof, wherein

-   R¹ is CH₃ or CH₂CH₃, and R^(1′) is hydrogen; or R¹ and R^(1′) are    taken together with the carbon atom to which they are attached to    form cyclopropyl; and R² is C₃₋₆alkyl and R³ is C₁₋₄alkyl;-   R⁴ is C₁₋₆alkyl; polyhaloC₁₋₄alkyl; C₃₋₆cycloalkyl; C₁₋₄alkyl    substituted with one C₃₋₆cycloalkyl; or NR⁷R⁸ wherein R⁷ is selected    from hydrogen and C₁₋₄alkyl; R⁸ is C₁₋₄alkyl or C₃₋₆cycloalkyl; or    R⁷ and R⁸ are taken together with the nitrogen to which they are    attached to form azetidinyl, pyrrolidinyl or piperidinyl;-   R⁵ is C₃₋₆cycloalkyl; Heteroaryl; naphthyl substituted with 1, 2 or    3 substituents each independently selected from halo and    hydroxycarbonyl; phenyl substituted with 1, 2 or 3 substituents each    independently selected from hydroxy; halo; C₁₋₆alkyl; C₁₋₆alkyl    substituted with one substituent selected from hydroxy,    hydroxycarbonyl and aminocarbonyl; C₃₋₆alkenyl; C₃₋₆alkenyl    substituted with one or two substituents selected from C₁₋₆alkyl,    hydroxy, hydroxycarbonyl and aminocarbonyl; C₃₋₆alkynyl; C₃₋₆alkynyl    substituted with one hydroxycarbonyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl    substituted with one hydroxycarbonyl; C₃₋₆cycloalkenyl;    C₃₋₆cycloalkenyl substituted with one hydroxycarbonyl; C₁₋₆alkyloxy;    polyhaloC₁₋₄alkyl; cyano; nitro; B(OH)₂; hydroxycarbonyl; CO—NHOH;    CO—NR⁹R¹⁰; CO—NH—NR⁹R¹⁰; NR⁹ R¹⁰ ; NH—CO—R¹¹; NH—CO—O—R¹¹;    NH—CO—NH—R¹¹; NH—CS—NH—R¹¹; NH—C═(N—CN)—NH—R¹¹; aminosulfonyl; mono-    or di(C₁₋₄alkyl)aminosulfonyl; and Heterocycle;-   wherein-   R⁹ and R¹⁰ are each independently selected from hydrogen; C₁₋₆alkyl;    SO₂—R¹²; and C₁₋₆alkyl substituted with hydroxy, hydroxycarbonyl,    C₃₋₆cycloalkyl, C₁₋₄alkylcarbonylamino, mono- or di(C₁₋₄alkyl)amino,    or Heterocycle;-   R¹¹ is C₁₋₆alkyl; C₃₋₆alkenyl; C₃₋₆cycloalkyl; Aryl; Heterocycle; or    C₁₋₆alkyl substituted with one substituent selected from    C₃₋₆cycloalkyl, C₁₋₄alkyloxy, hydroxy, cyano, hydroxycarbonyl,    aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl,    C₁-₄alkylcarbonylamino, and Heterocycle;-   R¹² is C₃₋₆cycloalkyl, or C₁₋₄alkyl substituted with one    C₃₋₆cycloalkyl,-   Heteroaryl is thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl,    1-benzopyrazolyl, 2,3-dihydro-1H-indolyl,    2-oxo-2,3-dihydro-1H-indolyl, quinolinyl, 2-oxo-quinolinyl,    benzimidazolyl, cinnolinyl, or 2H-chromenyl, wherein each Heteroaryl    is optionally substituted with one or two substituents each    independently selected from C₁₋₄alkyl, halo, amino, aminocarbonyl,    and NH—CO—C₃₋₆cycloalkyl;-   Heterocycle is azetidinyl, tetrahydrofuranyl, pyrrolidinyl, furanyl,    thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 2-oxo-azepanyl, 2,5-dioxo-pyrrolidinyl, or    3-oxo-2,3-dihydro-1,2-oxazolyl; wherein each Heterocycle is    optionally substituted with one or two substituents each    independently selected from C₃₋₆cycloalkyl, halo and    hydroxycarbonyl;-   Aryl is phenyl substituted with one or two substituents each    independently selected from hydrogen, halogen, C₁₋₄alkyl,    C₁₋₄alkyloxy, and trifluoromethyl;-   or a pharmaceutically acceptable acid addition salt thereof.

A third group of compounds are compounds of formula (I-c)

including any stereochemically isomeric form thereof, wherein

-   R⁶ is hydrogen, halo or C₁₋₄alkyl;-   the

moiety is a radical of formula:

wherein R¹ is CH₃ or CH₂CH₃, and R^(1′) is hydrogen; or R^(1′) is absentin radical (a-6); or R¹ and R^(1′) are taken together with the carbonatom to which they are attached to form cyclopropyl; and radical (a-1)to (a-15) are optionally substituted with one or two substituents eachindependently selected from C₁₋₂alkyl and halo;

-   R⁴ is C₁₋₆alkyl; polyhaloC₁₋₄alkyl; C₃₋₆cycloalkyl; C₁₋₄alkyl    substituted with one C₃₋₆cycloalkyl; or NR⁷R⁸ wherein R⁷ is selected    from hydrogen and C₁₋₄alkyl; R⁸ is C₁₋₄alkyl or C₃₋₆cycloalkyl; or    R⁷ and R⁸ are taken together with the nitrogen to which they are    attached to form azetidinyl, pyrrolidinyl or piperidinyl;-   R⁵ is C₃₋₆cycloalkyl; Heteroaryl; naphthyl substituted with 1, 2 or    3 substituents each independently selected from halo and    hydroxycarbonyl; phenyl substituted with 1, 2 or 3 substituents each    independently selected from hydroxy; halo; C₁₋₆alkyl; C₁₋₆alkyl    substituted with one substituent selected from hydroxy,    hydroxycarbonyl and aminocarbonyl; C₃₋₆alkenyl; C₃₋₆alkenyl    substituted with one or two substituents selected from C₁₋₆alkyl,    hydroxy, hydroxycarbonyl and aminocarbonyl; C₃₋₆alkynyl; C₃₋₆alkynyl    substituted with one hydroxycarbonyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl    substituted with one hydroxycarbonyl; C₃₋₆cycloalkenyl;    C₃₋₆cycloalkenyl substituted with one hydroxycarbonyl; C₁₋₆alkyloxy;    polyhaloC₁₋₄alkyl; cyano; nitro; B(OH)₂; hydroxycarbonyl; CO—NHOH;    CO—NR⁹R¹⁰; CO—NH—NR⁹R¹⁰; NR⁹R¹⁰; NH—CO—R¹¹; NH—CO—O—R¹¹;    NH—CO—NH—R¹¹; NH—CS—NH—RH; NH—C═(N—CN)—NH—R¹¹; aminosulfonyl; mono-    or di(C₁₋₄alkyl)aminosulfonyl; and Heterocycle;-   wherein-   R⁹ and R¹⁰ are each independently selected from hydrogen; C₁₋₆alkyl;    SO₂—R¹²; and C₁₋₆alkyl substituted with hydroxy, hydroxycarbonyl,    C₃₋₆cycloalkyl, C₁₋₄alkylcarbonylamino, mono- or di(C₁₋₄alkyl)amino,    or Heterocycle;-   R¹¹ is C₁₋₆alkyl; C₃₋₆alkenyl; C₃₋₆cycloalkyl; Aryl; Heterocycle; or    C₁₋₆alkyl substituted with one substituent selected from    C₃₋₆cycloalkyl, C₁₋₄alkyloxy, hydroxy, cyano, hydroxycarbonyl,    aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl,    C₁₋₄alkylcarbonylamino, and Heterocycle;-   R¹² is C₃₋₆cycloalkyl, or C₁₋₄alkyl substituted with one    C₃₋₆cycloalkyl,-   Heteroaryl is thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl,    1-benzopyrazolyl, 2,3-dihydro-1H-indolyl,    2-oxo-2,3-dihydro-1H-indolyl, quinolinyl, 2-oxo-quinolinyl,    benzimidazolyl, cinnolinyl, or 2H-chromenyl, wherein each Heteroaryl    is optionally substituted with one or two substituents each    independently selected from C₁₋₄alkyl, halo, amino, aminocarbonyl,    and NH—CO—C₃₋₆cycloalkyl;-   Heterocycle is azetidinyl, tetrahydrofuranyl, pyrrolidinyl, furanyl,    thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 2-oxo-azepanyl, 2,5-dioxo-pyrrolidinyl or    3-oxo-2,3-dihydro-1,2-oxazolyl; wherein each Heterocycle is    optionally substituted with one or two substituents each    independently selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, halo and    hydroxycarbonyl;-   Aryl is phenyl substituted with one or two substituents each    independently selected from hydrogen, halogen, C₁₋₄alkyl,    C₁₋₄alkyloxy, and trifluoromethyl;-   with the proviso that    [7-ethyl-2-(3-thienyl)pyrazolo[1,5-a]pyrimidin-5-yl](2-methyl-1-piperidinyl)-methanone    and    [7-ethyl-2-(2-pyridinyl)pyrazolo[1,5-a]pyrimidin-5-yl](2-methyl-1-piperidinyl)-methanone    are not included;-   or a pharmaceutically acceptable acid addition salt thereof.

A fourth group of compounds are compounds of formula (I-d)

including any stereochemically isomeric form thereof, wherein the

moiety is a radical of formula:

wherein R¹ is CH₃ or CH₂CH₃, and R^(1′) is hydrogen; or R^(1′) is absentin radical (a-6);

-   or R¹ and R^(1′) are taken together with the carbon atom to which    they are attached to form cyclopropyl; and radical (a-1) to (a-15)    are optionally substituted with one or two substituents each    independently selected from C₁₋₂alkyl and halo;-   R⁴ is C₁₋₆alkyl; polyhaloC₁₋₄alkyl; C₃₋₆cycloalkyl; C₁₋₄alkyl    substituted with one C₃₋₆cycloalkyl; or NR⁷R⁸ wherein R⁷ is selected    from hydrogen and C₁₋₄alkyl; R⁸ is C₁₋₄alkyl or C₃₋₆cycloalkyl; or    R⁷ and R⁸ are taken together with the nitrogen to which they are    attached to form azetidinyl, pyrrolidinyl or piperidinyl;-   R⁵ is C₃₋₆cycloalkyl; Heteroaryl; naphthyl substituted with 1, 2 or    3 substituents each independently selected from halo and    hydroxycarbonyl; phenyl substituted with 1, 2 or 3 substituents each    independently selected from hydroxy; halo; C₁₋₆alkyl; C₁₋₆alkyl    substituted with one substituent selected from hydroxy,    hydroxycarbonyl and aminocarbonyl; C₃₋₆alkenyl; C₃₋₆alkenyl    substituted with one or two substituents selected from C₁₋₆alkyl,    hydroxy, hydroxycarbonyl and aminocarbonyl; C₃₋₆alkynyl; C₃₋₆alkynyl    substituted with one hydroxycarbonyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl    substituted with one hydroxycarbonyl; C₃₋₆cycloalkenyl;    C₃₋₆cycloalkenyl substituted with one hydroxycarbonyl; C₁₋₆alkyloxy;    polyhaloC₁₋₄alkyl; cyano; nitro; B(OH)₂; hydroxycarbonyl; CO—NHOH;    CO—NR⁹R¹⁰; CO—NH—NR⁹R¹⁰; NR⁹R¹⁰; NH—CO—R¹¹; NH—CO—O—R¹¹;    NH—CO—NH—R¹¹; NH—CS—NH—RH; NH—C═(N—CN)—NH—R¹¹; aminosulfonyl; mono-    or di(C₁₋₄alkyl)aminosulfonyl; and Heterocycle;-   wherein-   R⁹ and R¹⁰ are each independently selected from hydrogen; C₁₋₆alkyl;    SO₂—R¹²; and C₁₋₆alkyl substituted with hydroxy, hydroxycarbonyl,    C₃₋₆cycloalkyl, C₁₋₄alkylcarbonylamino, mono- or di(C₁₋₄alkyl)amino,    or Heterocycle;-   R¹¹ is C₁₋₆alkyl; C₃₋₆alkenyl; C₃₋₆cycloalkyl; Aryl; Heterocycle; or    C₁₋₆alkyl substituted with one substituent selected from    C₃₋₆cycloalkyl, C₁₋₄alkyloxy, hydroxy, cyano, hydroxycarbonyl,    aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl,    C₁₋₄alkylcarbonylamino, and Heterocycle;-   R¹² is C₃₋₆cycloalkyl, or C₁₋₄alkyl substituted with one    C₃₋₆cycloalkyl,-   Heteroaryl is thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl,    1-benzopyrazolyl, 2,3-dihydro-1H-indolyl,    2-oxo-2,3-dihydro-1H-indolyl, quinolinyl, 2-oxo-quinolinyl,    benzimidazolyl, cinnolinyl, or 2H-chromenyl, wherein each Heteroaryl    is optionally substituted with one or two substituents each    independently selected from C₁₋₄alkyl, halo, amino, aminocarbonyl,    and NH—CO—C₃₋₆cycloalkyl;-   Heterocycle is azetidinyl, tetrahydrofuranyl, pyrrolidinyl, furanyl,    thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 2-oxo-azepanyl, 2,5-dioxo-pyrrolidinyl, or    3-oxo-2,3-dihydro-1,2-oxazolyl; wherein each Heterocycle is    optionally substituted with one or two substituents each    independently selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, halo and    hydroxycarbonyl;-   Aryl is phenyl substituted with one or two substituents each    independently selected from hydrogen, halogen, C₁₋₄alkyl,    C₁₋₄alkyloxy, and trifluoromethyl;-   or a pharmaceutically acceptable acid addition salt thereof.

A fifth group of compounds are those compounds of formula (I), includingany stereochemically isomeric form thereof, wherein

-   X is CR⁶ wherein R⁶ is hydrogen;-   the

moiety is a radical of formula:

wherein R¹ is CH₃, and RI: is hydrogen;

-   R⁴ is C₁₋₆alkyl; C₃₋₆alkenyl, polyhaloC₁₋₄alkyl; C₁₋₄alkyl    substituted with one C₃₋₆cycloalkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl    substituted with one or two substituents each individually selected    from hydroxy, halo, cyano, C₁₋₄alkyloxy, polyhaloC₁₋₄alkyl, and    polyhaloC₁₋₄alkyloxy;-   R⁵ is naphthyl substituted with 1, 2 or 3 substituents each    independently selected from halo and hydroxycarbonyl; or    -   phenyl substituted with 1, 2 or 3 substituents each        independently selected from hydroxy;        -   halo;        -   C₁-₆alkyl;        -   C₁₋₆alkyl substituted with one, two or three substituents            each independently selected from halo, hydroxy,            hydroxycarbonyl, aminocarbonyl, Heterocycle, C₃₋₆cycloalkyl,            C₃₋₆cycloalkyl substituted with one or two substituents each            independently selected from C₁₋₄alkyl, halo,            hydroxycarbonyl, and C₁₋₄alkyl substituted with            hydroxycarbonyl;        -   C₃₋₆alkenyl;        -   C₃₋₆alkenyl substituted with one or two substituents            selected from C₁₋₆alkyl, hydroxy, hydroxycarbonyl and            aminocarbonyl;        -   C₃₋₆alkynyl;        -   C₃₋₆alkynyl substituted with one hydroxycarbonyl;        -   C₃₋₆cycloalkyl;        -   C₃₋₆cycloalkyl substituted with one, two or three            substituents each independently selected from C₁₋₄alkyl,            halo, hydroxycarbonyl, and C₁₋₄alkyl substituted with            hydroxycarbonyl; C₃₋₆cycloalkenyl;        -   C₃₋₆cycloalkenyl substituted with one hydroxycarbonyl;        -   C₁₋₆alkyloxy optionally substituted with hydroxycarbonyl;        -   polyhaloC₁₋₄alkyl;        -   polyhaloC₁₋₄alkyloxy; or        -   Heterocycle;-   wherein-   Heterocycle is azetidinyl, tetrahydrofuranyl, pyrrolidinyl, furanyl,    thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl,    1,2,4-oxadiazolyl, 2,5-dihydro-1H-pyrrolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 2-oxo-azepanyl, 2,5-dioxopyrrolidinyl, or    3-oxo-2,3-dihydro-1,2-oxazolyl; wherein each Heterocycle is    optionally substituted with one or two substituents each    independently selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, halo,    hydroxyC₁₋₄alkyl, polyhaloC₁₋₄alkyl, hydroxycarbonyl, and C₁₋₄alkyl    substituted with hydroxycarbonyl;    or a pharmaceutically acceptable acid addition salt thereof.

A sixth group of compounds are those compounds of formula (I), includingany stereochemically isomeric form thereof, wherein

-   X is CR⁶ wherein R⁶ is hydrogen;-   the

moiety is a radical of formula:

wherein R¹ is CH₃, and R^(1′) is hydrogen;

-   R⁴ is C₁₋₆alkyl; C₃₋₆alkenyl, polyhaloC₁₋₄alkyl; C₁₋₄alkyl    substituted with one C₃₋₆cycloalkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl    substituted with one or two substituents each individually selected    from hydroxy, halo, cyano, C₁₋₄alkyl, C₁₋₄alkyloxy,    polyhaloC₁₋₄alkyl, and polyhaloC₁₋₄alkyloxy; or NR⁷R⁸ wherein R⁷ and    R⁸ are taken together with the nitrogen to which they are attached    to form azetidinyl, pyrrolidinyl or piperidinyl;-   R⁵ is phenyl substituted with 1, 2 or 3 substituents each    independently selected from    -   hydroxy;    -   halo;    -   C₁₋₆alkyl;    -   C₁₋₆alkyl substituted with one, two or three substituents each        independently selected from halo, hydroxy, hydroxycarbonyl,        aminocarbonyl, Heterocycle, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl        substituted with one or two substituents each independently        selected from C₁₋₄alkyl, halo, hydroxycarbonyl, and C₁₋₄alkyl        substituted with hydroxycarbonyl;    -   C₃₋₆alkenyl;    -   C₃₋₆alkenyl substituted with one or two substituents selected        from C₁₋₆alkyl, hydroxy, hydroxycarbonyl and aminocarbonyl;    -   C₃₋₆alkynyl;    -   C₃₋₆alkynyl substituted with one hydroxycarbonyl;    -   C₃₋₆cycloalkyl;    -   C₃₋₆cycloalkyl substituted with one, two or three substituents        each independently selected from C₁₋₄alkyl, halo,        hydroxycarbonyl, and C₁₋₄alkyl substituted with hydroxycarbonyl;    -   C₃₋₆cycloalkenyl;    -   C₃₋₆cycloalkenyl substituted with one hydroxycarbonyl;    -   C₁₋₆alkyloxy optionally substituted with hydroxycarbonyl;    -   polyhaloC₁₋₄alkyl; or    -   polyhaloC₁₋₄alkyloxy;    -   Heterocycle;    -   wherein    -   Heterocycle is azetidinyl, tetrahydrofuranyl, pyrrolidinyl,        furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl,        isoxazolyl, 1,2,4-oxadiazolyl, 2,5-dihydro-1H-pyrrolyl,        pyridinyl, pyrimidinyl, pyrazinyl, 2-oxo-azepanyl,        2,5-dioxopyrrolidinyl, or 3-oxo-2,3-dihydro-1,2-oxazolyl;        wherein each Heterocycle is optionally substituted with one or        two substituents each independently selected from C₁₋₄alkyl,        C₃₋₆cycloalkyl, halo, hydroxyC₁₋₄alkyl, polyhaloC₁₋₄alkyl,        hydroxycarbonyl, and C₁₋₄alkyl substituted with hydroxycarbonyl;-   or a pharmaceutically acceptable acid addition salt thereof.

A seventh group of compounds are those compounds of formula (I),including any stereochemically isomeric form thereof, wherein

-   X is CR⁶ wherein R⁶ is hydrogen;    the

moiety is a radical of formula:

wherein R¹ is CH₃, and R^(1′) is hydrogen;

-   R⁴ is C₁₋₆alkyl; C₃₋₆alkenyl, polyhaloC₁₋₄alkyl; C₁₋₄alkyl    substituted with one C₃₋₆cycloalkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl    substituted with one or two substituents each individually selected    from hydroxy, halo, cyano, C₁₋₄alkyloxy, polyhaloC₁₋₄alkyl, and    polyhaloC₁₋₄alkyloxy;-   R⁵ is phenyl substituted with 1, 2 or 3 substituents each    independently selected from    -   hydroxy;    -   halo;    -   C₁₋₆alkyl;    -   C₁₋₆alkyl substituted with one, two or three substituents each        independently selected from halo, hydroxy, hydroxycarbonyl,        aminocarbonyl, Heterocycle, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl        substituted with one or two substituents each independently        selected from C₁₋₄alkyl, halo, hydroxycarbonyl, and C₁₋₄alkyl        substituted with hydroxycarbonyl;    -   C₃₋₆alkenyl;    -   C₃₋₆alkenyl substituted with one or two substituents selected        from C₁₋₆alkyl, hydroxy, hydroxycarbonyl and aminocarbonyl;    -   C₃₋₆alkynyl;    -   C₃₋₆alkynyl substituted with one hydroxycarbonyl;    -   C₃₋₆cycloalkyl;    -   C₃₋₆cycloalkyl substituted with one, two or three substituents        each independently selected from C₁₋₄alkyl, halo,        hydroxycarbonyl, and C₁₋₄alkyl substituted with hydroxycarbonyl;    -   C₃₋₆cycloalkenyl;    -   C₃₋₆cycloalkenyl substituted with one hydroxycarbonyl;    -   C₁₋₆alkyloxy optionally substituted with hydroxycarbonyl;    -   polyhaloC₁₋₄alkyl; or    -   polyhaloC₁₋₄alkyloxy;-   or a pharmaceutically acceptable acid addition salt thereof.

An eight group of compounds are compounds of formula (I-e)

including any stereochemically isomeric form thereof, wherein

-   R⁴ is C₁₋₆alkyl; C₃₋₆alkenyl, polyhaloC₁₋₄alkyl; C₁₋₄alkyl    substituted with one C₃₋₆cycloalkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl    substituted with one or two substituents each individually selected    from hydroxy, halo, cyano, C₁₋₄alkyl; C₁₋₄alkyloxy,    polyhaloC₁₋₄alkyl, and polyhaloC₁₋₄alkyloxy-   R⁵ is naphthyl substituted with 1, 2 or 3 substituents each    independently selected from    -   halo and hydroxycarbonyl; or    -   phenyl substituted with 1, 2 or 3 substituents each        independently selected from        -   hydroxy;        -   halo;        -   C₁₋₆alkyl;        -   C₁₋₆alkyl substituted with one, two or three substituents            each independently selected from halo, hydroxy,            hydroxycarbonyl, aminocarbonyl, Heterocycle, C₃₋₆cycloalkyl,            C₃₋₆cycloalkyl substituted with one or two substituents each            independently selected from C₁₋₄alkyl, halo,            hydroxycarbonyl, and C₁₋₄alkyl substituted with            hydroxycarbonyl;        -   C₃₋₆alkenyl;        -   C₃₋₆alkenyl substituted with one or two substituents            selected from C₁₋₆alkyl, hydroxy, hydroxycarbonyl and            aminocarbonyl;        -   C₃₋₆alkynyl;        -   C₃₋₆alkynyl substituted with one hydroxycarbonyl;        -   C₃₋₆cycloalkyl;        -   C₃₋₆cycloalkyl substituted with one, two or three            substituents each independently selected from C₁₋₄alkyl,            halo, hydroxycarbonyl, and C₁₋₄alkyl substituted with            hydroxycarbonyl;        -   C₃₋₆cycloalkenyl;        -   C₃₋₆cycloalkenyl substituted with one hydroxycarbonyl;        -   C₁₋₆alkyloxy optionally substituted with hydroxycarbonyl;            polyhaloC₁₋₄alkyl;        -   polyhaloC₁₋₄alkyloxy; or        -   Heterocycle;-   wherein-   Heterocycle is azetidinyl, pyrrolidinyl, pyrazolyl or pyridinyl;    wherein each Heterocycle is optionally substituted with one or two    substituents each independently selected from C₃₋₆cycloalkyl, halo,    hydroxyC₁₋₄alkyl, polyhaloC₁₋₄alkyl, hydroxycarbonyl, and C₁₋₄alkyl    substituted with hydroxycarbonyl;-   or a pharmaceutically acceptable acid addition salt thereof.

A ninth group of compounds are compounds of formula (I-f)

including any stereochemically isomeric form thereof, wherein the

moiety is a radical of formula:

wherein R¹ is CH₃, and R^(1′) is hydrogen;

-   R⁴ is C₁₋₆alkyl; C₃₋₆alkenyl, polyhaloC₁₋₄alkyl; C₁₋₄alkyl    substituted with one C₃₋₆cycloalkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl    substituted with one or two substituents each individually selected    from hydroxy, halo, cyano, C₁₋₄alkyl, C₁₋₄alkyloxy,    polyhaloC₁₋₄alkyl, and polyhaloC₁₋₄alkyloxy-   R¹³ is C₃₋₆alkenyl substituted with one or two substituents selected    from C₁₋₆alkyl, hydroxy, hydroxycarbonyl and aminocarbonyl;    -   C₃₋₆cycloalkyl substituted with one, two or three substituents        each independently selected from C₁₋₄alkyl, halo,        hydroxycarbonyl, and C₁₋₄alkyl substituted with hydroxycarbonyl;        or    -   Heterocycle;-   wherein-   Heterocycle is azetidinyl, pyrrolidinyl, pyrazolyl or pyridinyl;    wherein each Heterocycle is optionally substituted with one or two    substituents each independently selected from C₁₋₄alkyl,    C₃₋₆cycloalkyl, halo, hydroxyC₁₋₄alkyl, polyhaloC₁₋₄alkyl,    hydroxycarbonyl, and C₁₋₄alkyl substituted with hydroxycarbonyl;-   or a pharmaceutically acceptable acid addition salt thereof.

Interesting compounds of formula (I) are those compounds of formula (I)wherein one or more of the following restrictions apply :

-   a) X is N; or-   b) X is CR⁶ wherein R⁶ is hydrogen or halo; or-   c) R¹ is CH₃, and R^(1′) is hydrogen; or-   d) R¹ and R^(1′) are taken together with the carbon atom to which    they are attached to form cyclopropyl; or-   e) R³ is CH₃ or CH₂CH₃; or-   f) R⁴ is C₁₋₆alkyl in particular ethyl; or-   g) R⁴ is C₃₋₆cycloalkyl in particular cyclopropyl; or-   h) R⁵ is phenyl substituted with 1, 2 or 3 substituents each    independently selected from hydroxy; halo; C₁₋₆alkyl; C₁₋₆alkyl    substituted with one substituent selected from hydroxy,    hydroxycarbonyl and aminocarbonyl; C₃₋₆alkenyl; C₃₋₆alkenyl    substituted with one or two substituents selected from C₁₋₆alkyl,    hydroxy, hydroxycarbonyl and aminocarbonyl; C₃₋₆alkynyl; C₃₋₆alkynyl    substituted with one hydroxycarbonyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl    substituted with one hydroxycarbonyl; C₃₋₆cycloalkenyl;    C₃₋₆cycloalkenyl substituted with one hydroxycarbonyl; C₁₋₆alkyloxy;    polyhaloC₁₋₄alkyl; cyano; nitro; B(OH)₂; hydroxycarbonyl; CO—NHOH;    CO—NR⁹R¹⁰; CO—NH—NR⁹R¹⁰; NR⁹ R¹⁰ ; NH—CO—R¹¹; NH—CO—O—R¹¹;    NH—CO—NH—R¹¹; NH—CS—NH—R¹¹; NH—C═(N—CN)—NH—R¹¹; aminosulfonyl; mono-    or di(C₁₋₄alkyl)aminosulfonyl; and Heterocycle; or-   i) R⁵ is phenyl substituted with 1, 2 or 3 substituents each    independently selected from halo; or C₁₋₆alkyl substituted with one    substituent selected from hydroxy, hydroxycarbonyl and    aminocarbonyl; or-   j) R⁵ is phenyl substituted with 1, 2 or 3 substituents each    independently selected from halo, or C₃₋₆alkenyl substituted with    one or two substituents selected from C₁₋₆alkyl, hydroxy,    hydroxycarbonyl and aminocarbonyl; and-   k) R⁵ is phenyl substituted with 1, 2 or 3 substituents each    independently selected from halo, or C₃₋₆cycloalkyl substituted with    hydroxycarbonyl.

Specific examples of compounds of formula (I) are:

Compounds of formula (I) can generally be prepared by reacting anintermediate of formula (II) with an intermediate of formula (III) in areaction-inert solvent, such as dichloromethane or DMF, in the presentof a suitable reagent, such as BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate), and a base such as diisopropylethylamine ortriethylamine.

Other synthetic pathways for preparing compounds of formula (I) havebeen described in the experimental party as general methods ofpreparation and specific working examples.

The compounds of formula (I) may further be prepared by convertingcompounds of formula (I) into each other according to art-known grouptransformation reactions.

The starting materials and some of the intermediates are known compoundsand are commercially available or may be prepared according toconventional reaction procedures generally known in the art.

The compounds of formula (I) as prepared in the hereinabove describedprocesses may be synthesized in the form of racemic mixtures ofenantiomers which can be separated from one another following art-knownresolution procedures. Those compounds of formula (I) that are obtainedin racemic form may be converted into the corresponding diastereomericsalt forms by reaction with a suitable chiral acid. Said diastereomericsalt forms are subsequently separated, for example, by selective orfractional crystallization and the enantiomers are liberated therefromby alkali. An alternative manner of separating the enantiomeric forms ofthe compounds of formula (I) involves liquid chromatography using achiral stationary phase. Said pure stereochemically isomeric forms mayalso be derived from the corresponding pure stereochemically isomericforms of the appropriate starting materials, provided that the reactionoccurs stereospecifically. Preferably if a specific stereoisomer isdesired, said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

The compounds of formula (I) show antiviral properties. Viral infectionstreatable using the compounds and methods of the present inventioninclude those infections brought on by ortho- and paramyxoviruses and inparticular by human and bovine respiratory syncytial virus (RSV). Anumber of the compounds of this invention moreover are active againstmutated strains of RSV. Additionally, many of the compounds of thisinvention show a favorable pharmacokinetic profile and have attractiveproperties in terms of bioavailabilty, including an acceptablehalf-life, AUC and peak values and lacking unfavourable phenomena suchas insufficient quick onset and tissue retention.

The in vitro antiviral activity against RSV of the present compounds wastested in a test as described in the experimental part of thedescription, and may also be demonstrated in a virus yield reductionassay. The in vivo antiviral activity against RSV of the presentcompounds may be demonstrated in a test model using cotton rats asdescribed in Wyde et al. in Antiviral Research, 38, p. 31-42(1998).

Additionally the present invention provides pharmaceutical compositionscomprising at least one pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of formula (I). Alsoprovided are pharmaceutical compositions comprising a pharmaceuticallyacceptable carrier, a therapeutically active amount of a compound offormula (I), and another antiviral agent, in particular a RSV inhibitingcompound.

In order to prepare the pharmaceutical compositions of this invention,an effective amount of the particular compound, in base or acid additionsalt form, as the active ingredient is combined in intimate admixturewith at least one pharmaceutically acceptable carrier, which carrier maytake a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirably in unitary dosage form suitable, preferably, for oraladministration, rectal administration, percutaneous administration orparenteral injection.

For example in preparing the compositions in oral dosage form, any ofthe usual liquid pharmaceutical carriers may be employed, such as forinstance water, glycols, oils, alcohols and the like in the case of oralliquid preparations such as suspensions, syrups, elixirs and solutions;or solid pharmaceutical carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their easyadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral injection compositions, thepharmaceutical carrier will mainly comprise sterile water, althoughother ingredients may be included in order to improve solubility of theactive ingredient. Injectable solutions may be prepared for instance byusing a pharmaceutical carrier comprising a saline solution, a glucosesolution or a mixture of both. Injectable suspensions may also beprepared by using appropriate liquid carriers, suspending agents and thelike. In compositions suitable for percutaneous administration, thepharmaceutical carrier may optionally comprise a penetration enhancingagent and/or a suitable wetting agent, optionally combined with minorproportions of suitable additives which do not cause a significantdeleterious effect to the skin. Said additives may be selected in orderto facilitate administration of the active ingredient to the skin and/orbe helpful for preparing the desired compositions. These topicalcompositions may be administered in various ways, e.g., as a transdermalpatch, a spot-on or an ointment. Addition salts of the compounds offormula (I), due to their increased water solubility over thecorresponding base form, are obviously more suitable in the preparationof aqueous compositions.

It is especially advantageous to formulate the pharmaceuticalcompositions of the invention in dosage unit form for ease ofadministration and uniformity of dosage. “Dosage unit form” as usedherein refers to physically discrete units suitable as unitary dosages,each unit containing a predetermined amount of active ingredientcalculated to produce the desired therapeutic effect in association withthe required pharmaceutical carrier. Examples of such dosage unit formsare tablets (including scored or coated tablets), capsules, pills,powder packets, wafers, injectable solutions or suspensions,teaspoonfuls, tablespoonfuls and the like, and segregated multiplesthereof.

For oral administration, the pharmaceutical compositions of the presentinvention may take the form of solid dose forms, for example, tablets(both swallowable and chewable forms), capsules or gelcaps, prepared byconventional means with pharmaceutically acceptable excipients andcarriers such as binding agents (e.g. pregelatinised maize starch,polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like),fillers (e.g. lactose, microcrystalline cellulose, calcium phosphate andthe like), lubricants (e.g. magnesium stearate, talc, silica and thelike), disintegrating agents (e.g. potato starch, sodium starchglycollate and the like), wetting agents (e.g. sodium laurylsulphate)and the like. Such tablets may also be coated by methods well known inthe art.

Liquid preparations for oral administration may take the form of e.g.solutions, syrups or suspensions, or they may be formulated as a dryproduct for admixture with water and/or another suitable liquid carrierbefore use. Such liquid preparations may be prepared by conventionalmeans, optionally with other pharmaceutically acceptable additives suchas suspending agents (e.g. sorbitol syrup, methylcellulose,hydroxypropylmethylcellulose or hydrogenated edible fats), emulsifyingagents (e.g. lecithin or acacia), non aqueous carriers (e.g. almond oil,oily esters or ethyl alcohol), sweeteners, flavours, masking agents andpreservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).

Pharmaceutically acceptable sweeteners useful in the pharmaceuticalcompositions of the invention comprise preferably at least one intensesweetener such as aspartame, acesulfame potassium, sodium cyclamate,alitame, a dihydrochalcone sweetener, monellin, stevioside sucralose(4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose) or, preferably,saccharin, sodium or calcium saccharin, and optionally at least one bulksweetener such as sorbitol, mannitol, fructose, sucrose, maltose,isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey.Intense sweeteners are conveniently used in low concentrations. Forexample, in the case of sodium saccharin, the said concentration mayrange from about 0.04% to 0.1% (weight/volume) of the final formulation.The bulk sweetener can effectively be used in larger concentrationsranging from about 10% to about 35%, preferably from about 10% to 15%(weight/volume).

The pharmaceutically acceptable flavours which can mask the bittertasting ingredients in the low-dosage formulations are preferably fruitflavours such as cherry, raspberry, black currant or strawberry flavour.A combination of two flavours may yield very good results. In thehigh-dosage formulations, stronger pharmaceutically acceptable flavoursmay be required such as Caramel Chocolate, Mint Cool, Fantasy and thelike. Each flavour may be present in the final composition in aconcentration ranging from about 0.05% to 1% (weight/volume).Combinations of said strong flavours are advantageously used. Preferablya flavour is used that does not undergo any change or loss of tasteand/or color under the circumstances of the formulation.

The compounds of formula (I) may be formulated for parenteraladministration by injection, conveniently intravenous, intra-muscular orsubcutaneous injection, for example by bolus injection or continuousintravenous infusion. Formulations for injection may be presented inunit dosage form, e.g. in ampoules or multi-dose containers, includingan added preservative. They may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulating agents such as isotonizing, suspending, stabilizing and/ordispersing agents. Alternatively, the active ingredient may be presentin powder form for mixing with a suitable vehicle, e.g. sterile pyrogenfree water, before use.

The compounds of formula (I) may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter and/or otherglycerides.

In general it is contemplated that an antivirally effective daily amountwould be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administerthe required dose as two, three, four or more sub-doses at appropriateintervals throughout the day. Said sub-doses may be formulated as unitdosage forms, for example, containing 1 to 1000 mg, and in particular 5to 200 mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weight,sex, extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention. Theeffective daily amount ranges mentioned hereinabove are therefore onlyguidelines.

Also, the combination of another antiviral agent and a compound offormula (I) can be used as a medicine. Thus, the present invention alsorelates to a product containing (a) a compound of formula (I), and (b)another antiviral compound, as a combined preparation for simultaneous,separate or sequential use in antiviral treatment. The different drugsmay be combined in a single preparation together with pharmaceuticallyacceptable carriers. For instance, the compounds of the presentinvention may be combined with interferon-beta or tumor necrosisfactor-alpha in order to treat or prevent RSV infections. Otherantiviral compounds (b) to be combined with a compound of formula (I)for use in the treatment of RSV are RSV fusion inhibitors or RSVpolymerase inhibitors. Specific antiviral compounds for combination withany of the compounds of formula (I) that are useful in the treatment ofRSV are the RSV inhibiting compounds selected from ribavirin,4′-chloromethyl-2′-deoxy-3′,5′-di-O-isobutyryl-2′-fluorocytidine(ALS-8176),N-(2-((S)-2-(5-((S)-3-aminopyrrolidin-1-yl)-6-methylpyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carbonyl)-4-chlorophenyl)methanesulfonamide(GS-5806), MDT-637, BTA-9881, BMS-433771, YM-543403, A-60444,TMC-353121, RFI-641, CL-387626, MBX-300,3-({5-chloro-1-[3-(methylsulfonyl)propyl]-1H-benzimidazol-2-yl}methyl)-1-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one,3-[[7-chloro-3-(2-ethylsulfonyl-ethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-1-cyclopropyl-imidazo[4,5-c]pyridin-2-one, and3-({5-chloro-1-[3-(methylsulfonyl)propyl]-1H-indol-2-yl}methyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one.

The invention will hereinafter be illlustrated with reference to thefollowing, non-limiting examples.

Experimental Part A. Abbreviations

(CO₂Me)₂ dimethyl oxalate

(M+H)⁺ protonated molecular ion

AcCl acetyl chloride

AcOH acetic acid

Al₂O₃ aluminum oxide

APTS p-toluenesulfonic acid monohydrate

aq. aqueous

B₂pin₂/bispin bis(pinacolato)diboron

Boc tent-butyloxycarbonyl

Boc₂) di-tert-butyl dicarbonate

-   -   (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium

BOP

-   -   hexafluorophosphate - CAS [56602-33-6]

br broad

-   -   2-(di-tert-butylphosphino)-1-phenylpyrrole, CataCXium Pt®

CataCXium PtB®

-   -   CAS [672937-61-0]

cc concentrated

CDI carbonyldiimidazole

CH₃CN acetonitrile

CHCl₃ chloroform

CO carbon monoxide

CO₂ carbon dioxide

COMU®N-[1-(cy ano-2-ethoxy -2-oxoethylideneaminooxy)dimethylamino(morpholino)uronium hexafluorophosphate

CPME cyclopentyl methyl ether (CPME)

CrO₃ chromium(VI) oxide CAS [1333-82-0]

Cs₂CO₃ cesium carbonate

CuBr copper (I) bromide

CuCl copper(I) chloride

CuI copper(I) iodide

CuSO_(4.5)H₂O copper(II) sulfate pentahydrate

d doublet

DABCO 1,4-diazabicyclo[2.2.2]octane CAS [280-57-9]

DAST diethylaminosulfur trifluoride

DCM dichloromethane

DEAD 1,2-diazenedicarboxylic acid, 1,2-diethyl ester CAS [1972-28-7]

DIEA diisopropylethylamine

DIPE diisopropyl ether

DMA dimethylacetamide

DMAP 4-dimethylaminopyridine

DME 1,2-dimethoxyethane

DMF dimethylformamide

DMSO dimethyl sulfoxide

EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide - CAS [1892-57-5]

eq. equivalent

Et₂O diethyl ether

Et₃N triethylamine

EtOAc ethyl acetate

EtOH ethanol

-   -   benzylidene(1,3-dimesityl-4-imidazolin-2-ylidene)

Grubbs II (tricyclohexylphosphine) ruthenium dichloride; Grubbs catalyst2nd

-   -   generation CAS [223415-64-3]

H₂O water

H₂SO₄ sulfuric acid

-   -   O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium

HATU

-   -   hexafluorophosphate - CAS [148893-10-1]

HCl hydrochloric acid

HOAt 1-hydroxy-7-azabenzotriazole - CAS [39968-33-7]

HPLC high performance liquid chromatography

iPrNH₂ isopropylamine

IprOH ₂-propanol

K₂CO₃ potassium carbonate

K₃PO₄ potassium orthophosphate

KCN potassium cyanide

KOAc potassium acetate

KOH potassium hydroxide

LiAlH₄ lithium aluminium hydride

LiOH, H₂O lithium hydroxide monohydrate

m/z

Me methyl

MeLi methyllithium

MeOH methanol

Me-THF 2-methyl tetrahydrofuran

MgSO₄ magnesium sulfate

min minute(s)

rac-trans-N,N-dimethylcyclohexane-1,2-diamine

N,N′-DMEDA

CAS [61798-24-1]

N₂ nitrogen

Na₂CO₃ sodium carbonate

Na₂ SO₄ sodium sulfate

NaBH₃CN 1M in sodium cyanoborohydride 1M solution in THF

THF

NaBH₄ sodium borohydride

NaHCO₃ sodium bicarbonate

NaNO₂ sodium nitrite

NaOH sodium hydroxide

n-BuLi n-butyllithium

NH₄Cl ammonium chloride

NMP 1-methyl-2-pyrrolidinone

PCl₅ phosphorus pentachloride

Pd(OAc)₂ palladium(II) acetate

Pd(PPh₃)₄ tetrakis triphenylphosphine palladium(0)

Pd/C palladium on carbon (10%)

Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium CAS [51364-51-3]

-   -   dichloro [1,1′-bis(diphenylphosphino) ferrocene] palladium(II)

PdCl2(dppf)

-   -   CAS [72287-26-4]    -   dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)

PdCl₂(dppf)DCM

-   -   dichloromethane adduct CAS [95464-05-4]

PdCl2(dtbpf)palladium,[1,1′-bis[bis(1,1-dimethylethyl)phosphino]ferrocene-P,P′]dichloro CAS [95408-45-0]

PdCl2(PPh3) palladium(II)-bis(triphenylphosphine) dichloride CAS[13965-03-2]

POCl₃ phosphoryle chloride

PPh3 triphenylphosphine

PtO₂ platinum oxide

q quartet

Rh/C rhodium on activated carbon CAS [7440-16-6]

rt or RT room temperature

s singlet SnCl₂.2H₂O tin(II) chloride dihydrate CAS [10025-69-1]

SO₂ sulfur dioxide

t triplet

TBAF tetrabutylammonium fluoride CAS [429-41-4]

-   -   O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium

TBTU

-   -   tetrafluoroborate CAS [125700-67-6]

tBuOH tert-butanol

TEA triethylamine CAS [121-44-8]

TES triethylsilane CAS [617-86-7]

TFA trifluoroacetic acid

THF tetrahydrofuran

TMSCl trimethylsilyl chloride

-   -   9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene

XantPhos

-   -   CAS [161265-03-8]    -   bis(1,1-dimethylethyl)[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]-phosphine        CAS [564483-19-8]

tBuXPhos

XPhos 2,4′,6′-diisopropyl-1,1′-biphenyl-2-yldicyclohexylphosphine

-   -   bis(N,N-dimethylcarbamodithioato-κS,κS″)-(T-4)-zinc

ZIRAM®

-   -   CAS [137-30-4]

The stereochemical configuration for some compounds has been designatedas R* or S* (or *R or *S) when the absolute stereochemistry isundetermined although the compound itself has been isolated as a singlestereoisomer and is enantiomerically pure.

B. Synthesis of the Intermediates

Intermediate (A)

Intermediate (A1): CDI (3.77 g, 23 mmol), then EtOH (2.43 g, 53 mmol)were added to a solution of 5-bromo-3-chloro-2-pyridinecarboxylic acid(5 g, 21 mmol) in THF (100 mL). The reaction mixture was stirred at RTfor 24 hours. The solvent was evaporated and the residue was washed withwater and extracted with CHCl₃. The organic layer was separated, driedover sodium sulfate, filtered and evaporated. The residue was purifiedby column chromatography (silica gel, CHCl₃/ether (1/1)). The purefractions were collected and the solvent was evaporated to give 5.28 g(100%) of intermediate (A1).

Intermediate (B)

Intermediate (B1): n-BuLi (1.6M in hexane) (46.13 mL, 73.81 mmol) wasadded to THF (50 mL) at −78° C. then a solution of CH₃CN (3.86 mL, 73.81mmol) in THF (40 mL) was added dropwise. The resulting slurry wasstirred for 1 h at −78° C. then a solution ofmethyl-4-bromo-2-fluorobenzoate (8.6 g, 36.90 mmol) in THF (20 mL) wasadded. The reaction mixture was warmed to −45° C. and allowed to stirfor 15 min. The reaction was quenched with HCl N and extracted withEtOAc. The organic layer was separated, washed with water then brine,dried over magnesium sulfate and evaporated till dryness to give 8.69 g(97%) of intermediate (B1).

The following compounds were prepared according to the procedure above:

Intermediate (B12): Prepared according to the above procedure from2-[bis[(1,1-di-methylethoxy)carbonyl]amino]-4-Thiazolecarboxylic acidethyl ester CAS [930303-58-5]. The crude product was purified by columnchromatography (silica gel, CHCl₃). The pure fractions were collectedand the solvent was evaporated to give 7.44 g (86%) of intermediate(B12).

Intermediate (C)

Intermediate (C1): A mixture of intermediate (B 1) and hydrazine hydrate(6.10 mL, 107.71 mmol) in EtOH (175 mL) was stirred at 85° C. for 8hours. The mixture was cooled down to RT and evaporated till dryness.The residue was taken up in DCM and stirred at 0° C. for 15 min. Thesolid was filtered off, washed with DCM and dried (60° C., vacuum) togive 5.61 g (61%) of intermediate (C1).

Intermediate (C2): Hydrazine hydrate (7 mL, 140 mmol) was added to asolution of 2-fluoro-4-nitro-r3-oxo-benzenepropanenitrile CAS[276880-94-4] (9.5 g, 45.6 mmol) in EtOH (100 mL) and the resultingmixture was heated at reflux for 5 hours. After completion of thereaction, the solvent was evaporated till dryness. The precipitate wastaken up in water, filtered off, washed with water and dried to give7.15 g (71%) of intermediate (C2).

The following compounds were prepared according to the procedure above:

Intermediate (C12): A mixture of intermediate (B2) (1 g, 47 mmol) andhydrazine hydrate (1 mL) was heated at reflux in AcOH for 1 hour. Thesolvent was evaporated and the residue was taken up in water. The solidwas filtered off and dried to give 1.1 g (87%) of intermediate (C12).

Intermediate (C13): LiAlH₄ (1.0 g, 26.2 mmol) was added portionwise to asolution of methyl-4-(5-amino-1H-pyrazol-3-yl)-benzoate CAS[333337-29-4] (1.9 g, 8.7 mmol) in dry THF (50 mL) at 0° C., after thenthe reaction mixture was stirred for 6 hours. The reaction mixture wasquenched cold by dropwise addition of H₂O (2 mL) and NaOH (20%, 3 g).The resulting slurry was filtered, the solid was washed with EtOH andthe filtrate was evaporated to dryness to give 1.4 g (85%) ofintermediate (C13).

Intermediate (C14): N-chlorosuccinimide (300 mg, 2.25 mmol) was added toa mixture of intermediate (C2) (500 mg, 2.25 mmol) in CH₃CN (5 mL) andthe reaction mixture was stirred at RT overnight. The reaction mixturewas poured into water and extracted with EtOAc. The organic layer wasdried over sodium sulfate, filtered and the solvent was evaporated togive 570 mg (100%) of intermediate (C14).

Intermediate (C15): The mixture of intermediate (B11) (5.33 g, 20 mmol)and hydrazine hydrochloride (1.44 g, 21 mmol) in EtOH (50 mL) was heatedat reflux for 12 hours. The solvent was evaporated and the residue waswashed with water and extracted with EtOAc. The organic layer wasseparated, dried over sodium sulfate and evaporated to give 5.25 g (96%)of intermediate (C15).

Intermediate (D)

Intermediate (Dl): Intermediate (C1) (1.5 g, 5.86 mmol) andethyl-2,4-dioxohexanoate CAS [13246-52-1] (1.01 g, 5.86 mmol) in EtOH(15 mL) were heated at reflux overnight. While cooling down to RT,crystallization occurred. The mixture was cooled to 0° C., the solid wasfiltered off, washed with cold EtOH and dried (vacuum, 60° C.) to give1.85 g (81%) of intermediate (D1).

The following compounds were prepared according to the procedure above:

Reaction scheme:

Intermediate (D33): Intermediate (D9) (22.6 g, 0.06 mol) was dissolvedin MeOH (250 mL) and Pd/C (2.0 g) was added. The reaction mixture wasshaken for 2 hours at RT under hydrogen (1 bar). Then the solution wasfiltered through a pad of Celite® to remove the catalyst and thefiltrate was evaporated to give 17.8 g (86%) of intermediate (D33).

Intermediate (D34): A solution of sodium nitrite (4.1 g, 0.06 mol) inwater (10 mL) was added dropwise to a suspension of intermediate (D33)(17.8 g, 54 mmol) in HCl cc (27 mL) and AcOH (12 mL) at 0° C. Thereaction mixture was stirred at 0° C. for 1 hour until the entire solidhad dissolved. Then, toluene (100 mL) was added and the reaction mixturewas heated at 60° C. for 1 hour. The diazonium salt solution, still at0° C., was treated cautiously with solid NaHCO₃ to achieve pH 6-7. Thereaction mixture was then added dropwise over 15 min to a previouslyprepared solution of copper cyanide (preparation: CuSO₄, 5H₂O (17.5 g)in water (10 mL) was added to a solution of KCN (17.5 g) in water (100mL) at 0° C.). The reaction mixture was allowed to warm to RT, stirredovernight and then partitioned between EtOAc and water. The aqueouslayer was extracted with EtOAc (×3). The combined organic extracts weredried over sodium sulfate, filtered and evaporated. The residue waspurified by column chromatography (silica gel, DCM). The pure fractionswere collected and the solvent was evaporated to give 6.7 g (37%) ofintermediate (D34).

Intermediate (D35): A mixture of intermediate (D34) (6.7 g, 0.02 mol) inTFA/H₂SO₄ (70 mL, 4/1) was stirred at RT for 48 hours. Then, thereaction mixture was diluted with water and the precipitate was filteredoff, washed with water and dried to give 4.2 g (60%) of intermediate(D35).

Reaction scheme:

Intermediate (D36): TBTU (4.0 g, 12.0 mmol) was added to a mixture ofintermediate (D22) (3.5 g, 10.3 mmol), NH₄Cl (2.7 g, 50.0 mmol) and DIEA(10 mL, 60.0 mmol) in DCM (50 mL). The reaction mixture was stirred atRT overnight then partitioned between DCM and water. The aqueous layerwas extracted with DCM. The combined organic extracts were dried oversodium sulfate, filtered and evaporated. The residue was taken up withEt₂O and dried to give 3.25 g (94%) of intermediate (D36).

Intermediate (D37): EDC (0.13 g, 0.65 mmol) was added to a mixture ofintermediate (D22) (0.2 g, 0.59 mmol), methylamine hydrochloride (0.65mmol), HOAt (0.08 g, 0.59 mmol) and DIEA (0.15 mL, 0.88 mmol) in DCM (20mL). The reaction mixture was stirred at RT overnight. The reactionmixture was poured into water. The organic layer was separated, washedwith brine, dried over sodium sulfate, filtered and evaporated. Theresidue was purified by column chromatography (silica gel, DCM/EtOAc).The pure fractions were collected and the solvent was evaporated to give220 mg (quant.) of intermediate (D37).

Intermediate (D38): A mixture of 5-(2-fluorophenyl)-1H-Pyrazol-3-amineCAS [502132-86-7] (0.50 g, 2.8 mmol) and ethyla,y-dioxo-cyclohexanepentanoate CAS [1561966-01-5] (0.746 g, 3.1 mmol)in dry EtOH (50 mL) was heated at reflux for 1 hour. After cooling downto RT, the precipitate was filtered off to give 0.82 g (77%) ofintermediate (D38).

Reaction scheme:

Intermediate (D39): Selectfluor^(R) (2.0 g, 5.6 mmol) was added to amixture of intermediate (D9) (1.0 g, 2.8 mmol) and NaHCO₃ (0.24 g, 2.8mmol) in CH₃CN (10 mL). The reaction mixture was stirred at RTovernight. Et₃N (0.8 mL, 5.6 mmol) was added and the reaction mixturewas stirred at RT for 2 hours. The reaction mixture was evaporated, thenthe residue was dissolved in DCM and washed with water. The organiclayer was separated, washed with brine, dried over sodium sulfate,filtered and evaporated. The residue was purified by columnchromatography (silica gel, DCM/EtOAc). The pure fractions werecollected and the solvent was evaporated to give 0.2 g (19%) ofintermediate (D39).

Alternative way when R^(b) is an amino group:

Intermediate (D40): A mixture of intermediate (I1) (1.5 g, 3.9 mmol),methylamine (2M in THF) (2.93 mL, 5.85 mmol) and Et₃N (1.63 mL, 11.70mmol) in CH₃CN (30 mL) was heated at reflux for 2 hours. The mixture wascooled down to RT, water was added and the product was extracted withDCM. The organic layer was dried over MgSO₄, filtered and the solventwas evaporated. The residue was taken up in EtOH, stirred on ice-bath,filtered and the precipitate was dried under vacuum (60° C.) to give1.24 g (83%) of intermediate (D40).

Intermediate (D41): Pyrrolidine (0.71 g, 10 mmol) was added to asuspension of intermediate (13) (1.52 g, 4.5 mmol) in CH₃CN (100 mL) at0° C., then the reaction mixture was stirred at RT for 3 hours. Thesolvent was evaporated (T<45° C.) and water was added to the residue.The precipitate was filtered off and dried to give 1.67 g (quant.) ofintermediate (D41).

The following compounds were prepared according to the above procedure:

Intermediate (D44): Dimethylamine (281 mg, 2.1 mmol) was added to asuspension of intermediate (12) (377 mg, 0.94 mmol) in CH₃CN (50 mL) at0° C. The reaction mixture was stirred at RT for 3 hours. The solventwas evaporated and water was added. The precipitate was filtered anddried to give 290 mg (75%) of intermediate (D44).

Intermediate (D45): A mixture of intermediate (I1) (5 g, 13 mmol),pyrrolidine (1.6 mL, 19.5 mmol) and Et₃N (5.42 mL, 39 mmol) in CH₃CN(100 mL) was refluxed for 4 hours. The mixture was cooled down to RT.Water was added, the mixture was stirred 30 min on an ice bath, theprecipitate was filtered off and dried under vacuum to afford 4.1 g(75%) of intermediate (D45).

Intermediate (D46): A mixture of intermediate (C1) (2.67 g, 10.4 mmol)and 4-cyclo-propyl-2-hydroxy-4-oxo 2-butenoic acid ethyl ester CAS[1021017-81-1] (2.5 g , 13.6 mmol) in EtOH (20 mL) was refluxed for 2hours then cooled to 5° C. and stirred for 1 hour. The precipitate wasfiltered off, washed with cold EtOH and dried (50° C., vacuum) to afford4.8 g of a residue. The residue was purified by column chromatography(silica gel, from Heptane/EtOAc 90/10 to 80/20). The pure fractions werecollected and evaporated to afford 3.1 g (73%) of intermediate (D46).

The following intermediates were prepared according to the aboveprocedure.

Intermediate (D47): A mixture of 5-bromo-1H-pyrazol-3-amine CAS[950739-21-6)] (65.8 g; 406 mmol) and 2-hydroxy-4-oxo-2-hexenoic acidmethyl ester CAS [91029-29-7] (74.4 g; 339 mmol) in MeOH (1.2 L) wasrefluxed for 18 hours. The mixture was cooled to RT and the precipitatewas filtered, washed with MeOH and dried to give 80.8 g of intermediate(D47) as a yellow crystals (first batch).The filtrate was evaporated andMeOH (200 mL) was added, the solid was filtered and the solid was washedwith MeOH (40 mL) and dried to give 6.1 g of intermediate (D47) asyellow solid (second batch). The filtrate was evaporated and MeOH (100mL) was added, the solid was filtered, washed with MeOH (20 mL) anddried to give 1.6 g intermediate (D47) (third batch). Global yield: 88.5g (92%) of intermediate (D47).

The following intermediates were prepared according to the aboveprocedure.

Reaction schema:

Intermediate (D48): Under N₂, in a Schlenk tube, bis(pinacolato)diboron(1.65 g; 6.50 mmol) and KOAc (1.06 g; 10.8 mmol) were added to asolution of intermediate (D47) (1.54 g; 5.41 mmol) in 1,4-dioxane (20mL). The solution was purged with nitrogen and charged with PdCl₂(dppf)(443 mg; 542 μmol). The resulting solution was purged again withnitrogen and stirred at 100° C. for 5 hours. The reaction mixture wascooled down to RT overnight. EtOAc and water were added. The twocombined layers were filtered on a frit. The precipitate was kept (167mg). The filtrate was decanted. Then the organic layer was washed withwater and brine (twice), dried over MgSO₄ and concentrated to give 1.5 gof a brown solid which was triturated in heptane. The precipitate wasfiltered to give 729 mg (63%) of intermediate (D48).

Reaction scheme for intermediate (D58):

Intermediate (D58): A solution of intermediate (I1) (1 g, 2.6 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(541.011 mg, 2.6 mmol) in K₂CO₃ (3.9 mL, 2 M, 7.8 mmol) and THF (10 mL)was degased with nitrogen for 10 min. PdCl₂(dppODCM (0.213 g, 0.26 mmol)was added and the resulting mixture was heated at 100° C. using a singlemode microwave (Biotage® initiator60) with a power output ranging from 0to 400 W for 20 min.The mixture was poured out into water, theprecipitate was filtered off, dried under vacuum to afford 850 mg ofintermediate (D58) as a crude product which was used in the next stepwithout further purification.

Intermediate (E)

Intermediate (El): A mixture of intermediate (D1) (3.7 g, 9.43 mmol) andKOH (2.65 g, 47.17 mmol) in EtOH (70 mL) was stirred at refluxovernight. The reaction mixture was cooled down to 0° C. and stirred for15 min. The precipitate was filtered off and dried (vacuum, 60° C.) togive 3.86 g (quant.) of intermediate (El) as carboxylate salt.

Intermediate (E2): KOH (1.3 g, 20 mmol) was added to a solution ofintermediate (D35) (4.2 g, 10 mmol) in EtOH (50 mL). The reactionmixture was stirred at RT for 1 hour. The solvent was evaporated and theresidue was extracted with water and washed with ether. The organiclayer was separated and the aqueous one was neutralized with HCl cc topH 7. The precipitate was filtered off and dried to give 3.8 g (99%) ofintermediate (E2).

The following intermediates were prepared according to the procedureabove:

Intermediate (E36): KOH (291 mg, 5.2 mmol) was added to a solution ofintermediate (D40) (985 mg, 2.6 mmol) in MeOH (50 mL). The reactionmixture was stirred at RT for 1 hour. The solvent was evaporated, thenthe residue was taken up with water and washed with ether. The aqueouslayer was neutralized with HCl cc to pH 7 and the precipitate wasfiltered off to give 0.90 g (95%) of intermediate (E36).

The compounds (E37) to (E41) were prepared according to the procedureabove.

Intermediate (E42): Intermediate (D26) (0.8 g, 2.21 mmol) was heated atreflux in HCl cc (5 mL) for 5 hours. After cooling down to RT, thereaction mixture was poured into water, then the precipitate wasfiltered off, washed with water and dried to give 0.6 g (81%) ofintermediate (E42).

Reaction scheme:

Intermediate (E43): Intermediate (C2) (0.75 g, 3.37 mmol) and1,1,1-trifluoropentane-2,4-dione CAS [367-57-7] (0.57 g, 3.70 mmol) wereheated at reflux in AcOH (20 mL) for 1 hour. The solvent was evaporatedand the residue was taken up with ether, the resulting precipitate wasfiltered off and dried to give 0.88 g (70%) of intermediate (E43).

Intermediate (E44): Intermediate (E43) (0.88 g, 2.58 mmol) and seleniumdioxide (1.1 g, 10 mmol) were heated at reflux in pyridine (20 mL) for24 hours. The reaction mixture was filtered through a short pad ofCelite®. The filtrate was evaporated, the residue was taken up in HCl1N. The solid was filtered off, washed with HCl 1N, then water and dried(on the air) to give 0.95 g (99%) of intermediate (E44).

Intermediate (E45): A mixture of intermediate (D45) (4.1 g, 9.78 mmol)and KOH (2.74 g, 48.9 mmol) in EtOH (40 mL) was refluxed overnight. Themixture was cooled down to 0° C., stirred for 15 min, the precipitatewas filtered off and dried (vacuum, 60° C.) to give 4.5 g (100%) ofintermediate (E45).

Intermediate (E46): KOH (0.74 g, 11.1 mmol) was dissolved in EtOH (40mL) then intermediate (D46) (1.5 g, 3.71 mmol) was added portionwise andthe suspension was refluxed for 4 hours then overnight at RT. Themixture was cooled down to 0° C., stirred for 15 min, the precipitatewas filtered off, washed twice with DIPE and dried (vacuum, 60° C.) togive 1.52g (98%) of intermediate (E46).

The following intermediates were prepared according to the aboveprocedure.

Reaction scheme:

Intermediate (E47): Intermediate (D47) (8.07 g; 28.4 mmol) was suspendedin EtOH (170 mL) then KOH (5.63 g; 85.2 mmol) was added and the reactionmixture was heated at reflux for 3 hours. The reaction mixture wasfiltered and the residual sticky solid was washed with Et₂O to give 8.25g (94%) of intermediate (E47) as a white solid.

The following intermediates were prepared according to the aboveprocedure.

Intermediate (E49): A solution of intermediate (D48) (100 mg; 0.402mmol), intermediate (R2) (121 mg; 0.402 mmol) and K₃PO₄ (256 mg; 1.21mmol) in 1,4-dioxane (2.9 mL) and water (878 μL) was purged with Nz.PdCl₂(dtbpf) (28 mg; 43.0 μmol) was added, the mixture was purged againwith N₂ and heated at 100° C. using one single mode microwave (Biotage®Initiator EXP 60) with a power output ranging from 0 to 400 W for 30min. The reaction mixture was concentrated to dryness to afford 472 mg(100%) of intermediate (E49) as brown oil. The product was used withoutfurther purification for the next step.

Intermediate (E54): Intermediate (I1) (0.5 g, 1.3 mmol) was put insuspension in EtOH (20 mL), then KOH (0.257 g, 3.9 mmol) was added andthe reaction mixture was heated to reflux for 2 h. The reaction mixturewas filtered and the residual sticky solid was dried under vaccum (60°C.) to afford 0.7 g of intermediate (E54).

The following intermediates were prepared according to intermediate(E54).

Intermediate (E62): A solution of LiOH.H₂O (0.327 g, 13.7 mmol) in H₂O(6 ml) was added to a solution of intermediate (D60) (3.50 g, 9.11 mmol)in THF (60 ml) at rt. The reaction mixture was stirred at rt for 16 h.Reaction mixture was concentrated under reduced pressure. EtOH was addedand the mixture was concentrated under reduced pressure. EtOH was addedand the solid was filtered, washed with Et₂O and dried to yield 2.60 g(77%) of intermediate (E62) as a lithium salt.

Intermediate (F)

Intermediate (FI): At 0° C., camphor (10 g, 66 mmol), then sodium azide(8.56 g, 132 mmol) were added small portionwise to a mixture ofmethanesulfonic acid (75 g) in CHCl₃ (200 mL).The reaction mixture wasstirred at 0° C. for 1 hour. Then, the reaction was warmed to RT,allowed stir for 2h and heated at reflux for 5 hours. The mixture wascooling down to RT, an aqueous solution of Na₂CO₃ was added to pH 8. Themixture was extracted with DCM, the organic layer was dried, filteredand evaporated to give intermediate (F1). The product was used withoutpurification for the next step.

Intermediate (F2): At −35° C., LiAlH₄ (5 g, 135 mmol) was added to asolution of intermediate (F1) in THF (150 mL). The reaction mixture wasstirred at −35° C. for 1 h30. Then, the reaction was warmed to RT,allowed stir for 2 h and heated at reflux for 5 hours. The mixture wascooling down to RT, water and 20% aqueous solution of NaOH were added.The mixture was filtered. HCl cc (10 mL) was added to the filtrate andthe solvent was evaporated. At 0° C., 30% aqueous solution of NaOH wasadded to a residue. The mixture was extracted with Et₂O, the organiclayer was separated, dried, filtered and evaporated. The residue waspurified by vacuum distillation (70° C., 20 torr) to give 1.4 g (14%) ofintermediate (F2).

Reaction scheme:

Intermediate (F3): Et₃N (12.8 g, 0.13 mol) and TMSC1 (12.1 g, 0.11 mol)were added to a solution of 1,4-dioxa-8-azaspiro[4.6]undecan-9-one CAS[172090-55-0] (17.3 g, 0.10 mol) in benzene (200 mL). The reactionmixture was stirred at RT for 20 hours. The mixture was filtered and thefiltrate was evaporated to give 23 g (90%) of intermediate (F3).

Intermediate (F4): At −30° C., MeLi (25 mmol) was added to a solution ofintermediate (F3) (6.1 g, 25 mmol) in Et₂O (100 mL). The reactionmixture was stirred at RT for 16 hours. Then, the aqueous solution ofNH₄Cl (1 g in 40 mL of water) was added and the mixture was extractedwith Et₂O. The organic layer was separated, dried over sodium sulfate,filtered and evaporated to give 4 g (94%) of intermediate (F4).

Intermediate (FS): NaBH4 (1.2 g) was added to a solution of intermediate(F4) in EtOH (30 mL). The reaction mixture was stirred at RT for 20hours. 10% aqueous solution of K₂CO₃ (50 mL) was added, the mixture wasstirred for 30min and extracted with DCM. The organic layer wasseparated, dried, filtered and evaporated to dryness. The residue waspurified by column chromatography to give 1.73 g (43%) of intermediate(F5).

Intermediate (F6): A solution of intermediate (F5) in HCl (10%) (30 mL)was stirred at RT for 48 hours. The reaction mixture was evaporated todryness and the residue was washed with Et₂O. The precipitate wasfiltered and dried to give 1.32 g (64%) of hydrochloride intermediate(F6).

Intermediate (F7): Boc20 (1.95 g, 8.3 mmol) and Et₃N (1.62 g, 16 mmol)were added to a solution of hydrochloride intermediate (F6) (1.32 g, 8.1mmol) in tBuOH (4 mL). The reaction mixture was stirred at 80° C. for 16hours. The solvent was evaporated to dryness and the residue was washedwith an aqueous solution of citric acid. The mixture was extracted withDCM. The organic layer was separated, dried, filtered and evaporated togive 1.4 g (76%) of intermediate (F7).

Intermediate (F8): DAST (2.4 g, 15 mmol) was added to a solution ofintermediate (F7) (1.4 g, 6.14 mmol) in DCM (4 mL) at RT. The reactionmixture was stirred at RT for 20 hours. 10% aqueous solution of K₂CO₃(50 mL) was added, the mixture was stirred for 30min and extracted withDCM. The organic layer was separated, dried, filtered and evaporated todryness. The residue was purified by column chromatography to give 1.4 g(86%) of intermediate (F8).

Intermediate (F9): HCl (4M in 1,4-dioxane) (3 mL) was added to asolution of intermediate (F8) (1.4 g, 5.3 mmol) in DCM (3 mL). Thereaction mixture was stirred at RT for 2 hours. The solvent wasevaporated to dryness and the residue was washed with ether. Theprecipitate was filtered and dried to give 0.6 g of hydrochlorideintermediate (F9).

Reaction scheme:

Intermediate (F10): Hydroxylamine hydrochloride (6.3 g, 91 mmol) and asolution of sodium acetate (7.5 g, 91 mmol) in water (40 mL) were addedto a solution of 7-methyl-1,4-dioxaspiro[4,5] decan-8-one CAS [702-69-2](7.2 g, 42.30 mmol) in MeOH (100 mL). The reaction mixture was stirredat RT for 20 hours. MeOH was evaporated and the mixture was extractedwith DCM. The organic layer was separated, dried, filtered andevaporated to give 7.3 g of intermediate (F10).

Intermediate (F11): Tosylchloride (13 g) and a solution of Na₂CO₃ (14.5g) in water (140 mL) were added to a solution of intermediate (F10) (7.3g) in THF (150 mL). The reaction was stirred at 50° C. for 20 hours. A10% aqueous solution of K₂CO₃ (50 mL) was added, the mixture was stirredfor 30 min and extracted with DCM. The organic layer was separated,dried, filtered and evaporated to dryness. The residue was purified bycolumn chromatography to give 1.7 g (22%) of intermediate (F11).

Intermediate (F12): At −30° C., LiAlH₄ (2 g, 54 mmol) was added to asolution of intermediate (F11) (1.7 g, 8.2 mmol) in THF (50 mL). Thereaction mixture was stirred at RT for 20 hours. Then, an aqueoussolution of NaOH was added and the mixture was filtered off. The cakewas washed with THF and the filtrate was evaporated to give 1.4 g ofintermediate (F12).

Intermediate (F13): A solution of intermediate (F12) in HCl (10%) (30mL) was stirred at RT for 48 hours. The reaction mixture was evaporatedto dryness and the residue was washed with Et₂O. The precipitate wasfiltered and dried to give 1.32 g (64%) of hydrochloride intermediate(F13)

Intermediate (F14): Boc20 (1.95 g, 8.3 mmol) and Et₃N (1.62 g, 16 mmol)were added to a solution of hydrochloride intermediate (F13) (1.32 g,8.1 mmol) in tBuOH (4 mL). The reaction mixture was stirred at 80° C.for 16 hours. The solvent was evaporated to dryness and the residue waswashed with an aqueous solution of citric acid. The mixture wasextracted with DCM. The organic layer was separated, dried, filtered andevaporated to give 1.4 g (76%) of intermediate (F14).

Intermediate (F15): DAST (2.4 g, 15 mmol) was added to a solution ofintermediate (F14) (1.4 g, 6.14 mmol) in DCM (4 mL) at RT. The reactionmixture was stirred at RT for 20 hours. 10% aqueous solution of K₂CO₃(50 mL) was added, the mixture was stirred for 30min and extracted withDCM. The organic layer was separated, dried, filtered and evaporated todryness. The residue was purified by column chromatography to give 1.4 g(86%) of intermediate (F15).

Intermediate (F16): HCl (4M in 1,4-dioxane) (3 mL) was added to asolution of intermediate (F15) (1.4 g, 5.3 mmol) in DCM (3 mL). Thereaction mixture was stirred at RT for 2 hours. The solvent wasevaporated to dryness and the residue was washed with ether. Theprecipitate was filtered and dried to give 0.6 g of hydrochlorideintermediate (F16).

Intermediate (F17): A solution of 3,3-di-2-propen-1-yl-2-piperidinone(9.0 g, 50.2 mmol) in DCM (200 ml) was degassed and Grubbs II (0.013 g,0.015 mmol) was added and the reaction was stirred at room temperaturefor 2 days and 40° C. for 10 h. The reaction was concentrated underreduced pressure. The crude oil was purified by preparative LC(irregular SiOH, 40-63 μm, Fluka®, mobile phase gradient: frompentane/Et₂O 50/50 to 0/100) to give silver solid. The solid wasdissolved in 10 mL of dichloromethane and 5 g of SilicaMetS DMT(Silicycle®, 40-63 μm, ruthenium scavenger) was added and stirred atroom temperature for 1 h. The scavenger was filtered off and thefiltrate was evaporated to give 6.52 g (86%) of intermediate (F17) aswhite solid.

Intermediate (F18): TMSC1 (1.7 mL, 13.4 mmol) was added dropwise to amixture of intermediate (F17) (2.0 g, 13.2 mmol) and TEA (2.8 mL, 19.8mmol) in toluene (25 ml) at rt. The resulting suspension was stirred at60° C. for 5 hours. Anhydrous diethyl ether (20 mL) and pentane (20 mL)were added and the solid was filtered on millipore filter. The filtratewas partially evaporated (pentane and Et₂O) to afford 15 ml of TMSadduct in residual toluene. This solution was added dropwise to MeLi1.6M in Et₂O (9.6 ml, 14.8 mmol) at −30° C. The resulting mixture wasstirred at −30° C. for 20 min and allowed to warm to room temperatureover 1 h. The reaction mixture was quenched by the addition of 20 ml ofsaturated aqueous NH₄Cl and extracted with Et₂O (2×40 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure to eliminate the diethyl ether and give a solution ofimine in toluene. This solution was diluted with DCM (30 mL) thenNaBH(OAc)₃ (3.50 g, 16.5 mmol) was added portionwise at 0° C. Themixture was stirred at rt for 16 h and quenched by the addition of 20 mlof saturated aqueous NH₄Cl and extracted with DCM (2×40 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, treated withHCl 4 M in dioxane (4.6 mL, 18.5 mmol) and concentrated under reducedpressure. The residue was purified by column chromatography (silica gel,mobile phase: DCM/MeOH/_(aq)NH₃ 90/10/1) to give 1.5 g (60%) ofintermediate (F18) as white solid.

Intermediate (F19): H₂O (2.00 mL) and then HCl 37% (2.20 mL, 26.8 mmol)were added dropwise with caution to stirred 1,3-Diaminopropane (6.17 g,83.2 mmol) at 0° C. (ice bath) followed by addition of 2-Furyl methylketone (4.00 g, 36.3 mmol). The resulting mixture was stirred at reflux(oil bath 120° C.) for 15 min then at rt for 45 min. K₂CO₃ (4 g) andwater (4 mL) were added and the mixture was extracted with DCM (3×25mL). The combined organic layers were washed with aq. K₂CO₃ (10 mL, 30wt %), dried over Na₂SO₄, filtered and concentrated under reducedpressure and purified by Preparative LC (neutral aluminum oxide (Typ507C, Brockmann I, 150 mesh, Sigma-Aldrich® 19,997-4); mobile phase:DCM/MeOH 100/0 to 98/2). The pure fractions were collected and thesolvent was evaporated to give 1.70 g of intermediate (F19) as yellowbrownish oil (32%).

Intermediate (F20): NaBH₄ (0.564 g, 14.9 mmol) was added portionwisewithin 10 min to a solution of intermediate (F19) (1.70 g, 11.5 mmol) inMeOH (11.5 mL) at 0° C. (ice-water bath). The resulting mixture wasstirred at rt for 2 hours and then concentrated under reduced pressure.The residue was taken in H₂O (20 mL) and extracted with DCM (3×20 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give 1.51 g (88%) of intermediate(F20) as an oil.

Intermediate (F21): In a Parr® reactor,(1R)-1,2,3,4-tetrahydro-1-methyl-Isoquinoline (2.00 g, 13.6 mmol) wasdissolved in AcOH (32 mL). PtO₂ (1.60 g, 7.06 mmol) was added and thereaction was purged 3 times with Hz. The reaction mixture was stirredunder 10 bar for 3 days. Catalyst was filtered off, the residue waswashed with AcOH and EtOAc and evaporated to dryness to give 4.46 g of acrude product as colourless oil. This oil was dissolved in toluene andcoevaporated twice to give 3.12 g of an intermediate which was dissolvedin MeOH (154 mL) and HCl 3M in CPME (34 mL) was added. The reactionmixture was stirred at 0° C. for 4 h. The reaction mixture wasevaporated in vacuo to give 3.90 g of intermediate (F21) as pale yellowsolid (quant.).

Intermediates (F22) and (F23):4,5,6,7-tetrahydro-4-methyl-thieno[3,2-c]pyridine was purified by chiralSFC (Stationary phase: Lux cellulose® 2 5 μm 250*21.2 mm, Mobile phase:80% CO₂, 20% iPOH(0.3% iPrNH2)) to give 2 fractions: 2 g of intermediate(F22) as a colorless oil (*R) and 2.1 g of intermediate (F23) as acolorless oil (*S).

Intermediate (G)

Intermediate (G1): A mixture of intermediate (El) (2 g, 4.97 mmol),(R)-2-methyl-azepane hydrochloride (0.893 g, 5.97 mmol), HATU (2.84 g,7.46 mmol) and DIEA (2.61 mL, 14.92 mmol) in DMF (20 mL) was stirredovernight at RT. The reaction mixture was poured into water (100 mL),the precipitate was filtered off, washed with water and dried (vacuum,60° C.). The residue (2.38 g, >100%) was purified by columnchromatography over silica gel (80g, 15-40 μm, eluent: from 80% heptane,20% EtOAc to 70% heptane, 30% EtOAc). The pure fractions were collectedand the solvent was evaporated to give 1.96 g (86%) of intermediate(G1).

The following intermediates were prepared according to the aboveprocedure:

Intermediate (G2): A mixture of intermediate (El) (8.19 g, 22.5 mmol),BOP (10.86 g, 25 mmol), DIEA (7.10 g, 56 mmol) and 2-methylazepanhydrochloride (3.46 g, 23.1 mmol) in dry DMF (50 mL) was stirred at RTfor 6 hours. The solvent was evaporated, then the residue was taken upwith CHCl₃ and washed with water. The organic layer was separated andevaporated till dryness. The crude product was purified by columnchromatography (silica gel, CHCl₃/EtOAc (14/1)). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom hexane/Et₂O (1/1) to give 8.62 g (85%) of intermediate (G2).

The following intermediates were prepared according to the aboveprocedure:

Intermediate (G8): A mixture of intermediate (E36) (0.90 g, 2.47 mmol),BOP (1.10 g, 2.7 mmol), DIEA (0.797 g, 6.2 mmol) and 2-methylazepanehydrochloride (0.388 g, 2.5 mmol) in dry DMF (25 mL) was stirred at RTfor 6 hours. The solvent was evaporated, then the residue was extractedwith CHCl₃ and washed with water. The organic layer was separated andevaporated till dryness. The residue was purified by columnchromatography (silica gel, CHCl₃/Et₂O). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom hexane/Et₂O (1/1) to give 0.72 g (64%) of intermediate (G8).

The following intermediates were prepared according to the aboveprocedure:

Intermediate (G13): TBTU (1.4 mmol) was added to a mixture ofintermediate (E10) (1.3 mmol), 2-methylazepane (1.4 mmol) and DIEA (3.2mmol) in DCM (50 mL). The reaction mixture was stirred at RT overnight.The mixture was poured into water, then the organic layer was separated,washed with brine, dried over sodium sulfate, filtered and the filtratewas evaporated. The residue was purified by column chromatography(silica gel, DCM). The pure fractions were collected and the solvent wasevaporated to give intermediate (G13).

The following intermediates were prepared according to the aboveprocedure:

Intermediate (G21): TBTU (0.18 g, 0.56 mmol) was added to a mixture ofintermediate (E33) (0.18 g, 0.5 mmol), 2-methylazepane hydrochloride(0.08 g, 0.56 mmol) and DIEA (0.25 mL, 1.5 mmol) in DCM (5 mL). Thereaction mixture was stirred at RT overnight. Water was added, then theorganic layer was separated, washed with brine, dried over sodiumsulfate, filtered and evaporated. The residue was purified by columnchromatography (silica gel, DCM). The pure fractions were collected andthe solvent was evaporated to give 0.23 g (99%) of intermediate (G21).

Intermediate (G22): TBTU (0.45 g, 1.4 mmol) was added to a mixture ofintermediate (E32) (0.49 g, 1.3 mmol), 2-methylazepane hydrochloride(0.21 g, 1.4 mmol) and DIEA (0.5 mL, 3.2 mmol) in DCM (50 mL). Thereaction mixture was stirred at RT overnight. Water was added, then theorganic layer was separated, washed with brine, dried over sodiumsulfate, filtered and evaporated. The residue was purified by columnchromatography (silica gel, DCM). The pure fractions were collected andthe solvent was evaporated to give 0.54 g (80%) of intermediate (G22).

Intermediate (G23): DIEA (0.48 g, 3.72 mmol) was added to a mixture ofintermediate (E44) (0.46 g, 1.24 mmol), 2-methylazepane hydrochloride(140 mg, 1.24 mmol), HOAt (0.243 g, 1.24 mmol) and EDC (0.356 g, 1.86mmol) in DCM. The reaction mixture was stirred at RT for 12 hours. Thereaction mixture was poured into water, extracted with DCM, dried oversodium sulfate, filtered and evaporated to dryness. The residue waspurified by column chromatography (silica gel, DCM/EtOAc (1/1)). Thepure fractions were collected and the solvent was evaporated to give 0.4g (88%) of intermediate (G23).

The following intermediates were prepared according to the aboveprocedure:

Reaction scheme:

Intermediate (G29): A mixture of intermediate (G2) (6.60 g, 14.4 mmol),KOAc (4.23 g, 43.2 mmol), bis(pinacolato)diboron (5.12 g, 20.1 mmol) andPdCl₂dppf (0.527 g, 7.2 mmol) in dry 1,4-dioxane was heated at refluxfor 48 hours. The reaction mixture was filtered through a pad of Celite®and the filtrate was evaporated under vacuum. The residue was purifiedby column chromatography (silica gel, CHCl₃). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedin hexane to give 5.15 g (71%) of intermediate (G29).

Intermediate (G30): A mixture of intermediate (G1) (8 g, 17.41 mmol),bispin (6.63 g, 26.12 mmol) and KOAc(5.13 g, 52.25 mmol) in Me-THF (60mL) was purged with N₂ flow for 10 min then PdCl2(dppf)DCM (1.42 g, 1.74mmol) was added. The resulting mixture was heated at 120° C. using asinglemode microwave (Biotage® initiator60) with a power output rangingfrom 0 to 400 W for 40 min. The mixture was poured out into water andEtOAc, the mixture was filtered through a short pad of Celite®, theorganic layer was separated, washed with brine, dried (MgSO₄) andevaporated till dryness. Purification of the crude product was carriedout by flash chromatography over silica gel (cartridge 120 g, 15-40 μm,Heptane/EtOAc 80/20). The pure fractions were collected and evaporatedto dryness to afford 7.5g (85%) of intermediate (G30). The product wasused as such for the next step.

Reaction scheme:

Intermediate (G31): Ethyl acrylate (330 mg, 3.3 mmol) was added to amixture of intermediate (G2) (300 mg, 0.65 mmol), PPh3 (100 mg, 0.33mmol), Pd(OAc)₂ (10 mg) and DIEA (0.4 mL, 6.5 mmol) in DMF (5 mL). Thereaction mixture was stirred at 100° C. for 5 hours. Then, the solutionwas poured into water and EtOAc was added. The organic layer wasseparated, washed with brine, dried over sodium sulfate, filtered andevaporated. The residue was purified by column chromatography (silicagel, DCM/EtOAc). The pure fractions were collected and the solvent wasevaporated to give 170 mg (55%) of intermediate (G31).

The following intermediates were prepared according to the aboveprocedure:

Intermediate (G43): Intermediate (G31) (514 mg, 1.1 mmol) was dissolvedin EtOH (10 mL) and Pd/C (0.1 g) was added. The mixture was shaken for16 h at RT under hydrogen (1 bar). Then the solution was filteredthrough a pad of Celite® to remove the catalyst and the filtrate wasevaporated. The residue was purified by column chromatography (silicagel, DCM/EtOAc). The pure fractions were collected and the solvent wasevaporated to give 0.16 g (31%) of intermediate (G43).

Intermediate (G44): A solution of diazomethane in Et₂O (prepared from0.5 g of N-nitrosomethylurea) was added to a solution of intermediate(G31) (0.11 g, 0.23 mmol) in Et₂O (10 mL). The reaction mixture wasstirred at RT for 4 hours. The mixture was evaporated and the residuewas purified by column chromatography to give 80 mg of intermediate(G44).

Reaction scheme:

Intermediate (G45): Intermediate (G13) (0.4 g, 0.9 mmol) was dissolvedin MeOH (50 mL) and Pd/C (0.1 g) was added. The mixture was shaken for 2hours at RT under hydrogen (1 bar). Then the solution was filteredthrough a pad of Celite® to remove the catalyst and the filtrate wasevaporated to give 0.35 g (99%) of intermediate (G45).

The following intermediates were prepared according to the aboveprocedure:

Intermediate (G49): Intermediate (G45) (0.6 g, 1.52 mmol) was dissolvedin a mixture of HCl cc (0.77 mL) and AcOH (0.39 mL). The solution wascooled to 0° C. and a solution of sodium nitrite (0.13 g, 1.9 mmol) inwater (2 mL) was added dropwise with stirring. After 30 min, thereaction mixture was added dropwise to a suspension of CuCl (77 mg, 0.77mmol) in saturated solution of SO₂ in AcOH (0.43 mL) at 5° C. Thereaction mixture was stirred for 30 min at 10° C. then poured intowater. The reaction mixture was extracted with EtOAc. The organic layerwas washed with saturated aqueous solution of NaHCO₃, then brine, driedover sodium sulfate, filtered and evaporated to give 0.25 g ofintermediate (G49).

Reaction scheme:

Intermediate (G50): TBTU (0.45 g, 1.39 mmol) was added to a mixture ofintermediate (G45) (0.5 g, 1.26 mmol), butanedioic acid 1-methyl ester(0.19 g, 1.39 mmol) and DIEA (0.3 mL, 1.9 mmol) in DCM (10 mL). Thereaction mixture was stirred at RT overnight. The reaction mixture waspoured into water. The organic layer was separated, washed with brine,dried over sodium sulfate, filtered and evaporated till dryness. Theresidue was purified by column chromatography (silica gel, DCM). Thepure fractions were collected and the solvent was evaporated to give 500mg (78%) of intermediate (G50).

Reaction scheme:

Intermediate (G51): Intermediate (G23) (0.35 g, 0.75 mmol) andSnCl₂.2H₂O (3eq.) in MeOH in presence of 1 drop of HCl cc were heated atreflux for 3 hours. The solvent was evaporated, water was added and themixture was extracted with DCM. The organic layer was dried over sodiumsulfate, filtered and evaporated under reduced pressure to give 0.3 g ofintermediate (G51).

Intermediate (G52): SnCl₂.2H₂O (710 mg, 3.1 mmol) was added to asolution of intermediate (G22) (0.47 g, 1.0 mmol) in MeOH (50 mL). Thereaction mixture was heated at reflux for 2h, then cooled andevaporated. A saturated aqueous solution of NaHCO₃ was added to theresidue and the mixture was extracted. The organic layer was separated,washed with brine, dried over sodium sulfate, filtered and evaporated togive 0.5 g (99%) of intermediate (G52).

Intermediate (G53): Sodium nitrite (55 mg, 0.80 mol) in water (3.5 mL)was added dropwise to a suspension of intermediate (G51) (0.3 g, 0.80mol) and HCl cc (1 mL) in water (1 mL) and CH₃CN (17 mL) at 0° C. Thereaction mixture was stirred at 0° C. for 1 h until the solid wasdissolved. Then, an aqueous solution of Na₂CO₃ was added till pH 6-7.Simultaneously, a solution of CuSO₄,5H₂O (0.3 g, 1.2 mol) in water (3mL) was added dropwise to a solution of KCN (0.3 g, 4.6 mol) in water (3mL) at 0° C. Toluene (12 mL) was then added and the reaction mixture washeated at 60° C. for 1 hour. The diazonium salt solution was addeddropwise over 15 min to this copper cyanide mixture at 60° C. Thereaction mixture was heated at 70° C. for 1.5h, allowed to cool down toRT, partitioned between EtOAc and water. The aqueous layer was extractedwith EtOAc (×3). The combined organic extracts were dried over sodiumsulfate, filtered and evaporated. The resulting solid was purified bycolumn chromatography (silica gel, DCM/EtOAc (5/1)). The pure fractionswere collected and the solvent was evaporated to give 0.05 g (14%) ofintermediate (G53).

Reaction scheme:

Intermediate (G54): HCl (3N in 1,4-dioxane) (1.0 mL, 3.0 mol) was addedto a stirred solution of intermediate (G24) (1.0 g, 2.0 mol) in1,4-dioxane (5 mL). The reaction mixture was stirred at RT for 12 hours.The solvent was evaporated and the residue was taken up with DCM and asaturated aqueous solution of Na₂CO₃ (pH 7). The organic layer wasseparated, dried over sodium sulfate, filtered and evaporated underreduced pressure. The residue was purified by column chromatography(silica gel, DCM/EtOAc). The pure fractions were collected and thesolvent was evaporated to give 0.8 g of intermediate (G54).

The following intermediates were prepared according to the aboveprocedure:

Reaction scheme:

Intermediate (G57): Pd(PPh₃)₄ (77 mg, 0.07 mmol) was added to a stirredsolution of intermediate (G27) (160 mg, 0.33 mmol), KCN (87 mg, 1.34mmol) and CuI (5 mg) in anhydrous CH₃CN (5 mL). The reaction mixture washeated at 160° C. for 2 h using one single mode microwave (Biotage®initiator60) with a power output ranging from 0 to 400 W. The solventwas evaporated. The residue was purified by column chromatography(silica gel, DCM/EtOAc). The pure fractions were collected and thesolvent was evaporated to give 120 mg (86%) of intermediate (G57).

The following intermediate was prepared according to the above procedure

Reaction scheme:

Intermediate (G59): TBTU (110 mg, 0.36 mmol) was added to a solution ofcompound (K1) (0.15 g, 0.33 mmol), methyl alanate hydrochloride (55 mg,0.39 mmol) and DIEA (0.13 g, 0.1 mmol) in DCM. The reaction mixture wasstirred at RT for 12 hours. The mixture was poured into water andextracted with DCM. The organic layer was separated, dried over sodiumsulfate, filtered and evaporated. The residue was purified by columnchromatography (silica gel, DCM/EtOAc (10/1)). The pure fractions werecollected and the solvent was evaporated to give 100 mg (32%) ofintermediate (G59).

Intermediate (G60): A mixture of intermediate (E36) (0.75 g, 1.86 mmol),(R)-1,2,3,4-tetrahydro-1-methylisoquinoline (0.33 g, 2.23 mmol), HATU(1.06 g, 2.79 mmol) and DIEA (0.9 mL, 5.58 mmol) in DMF (10 mL) wasstirred overnight at RT. The mixture was poured out into water,extracted twice with EtOAc. The organic layers were washed with waterthen brine, dried over MgSO4 and evaporated till dryness. The residuewas purified by column chromatography (silica gel, Heptane/AcOEt 70/30).The pure fractions were collected and evaporated to dryness to afford455 mg (49%) of intermediate (G60).

Intermediate (G61): A mixture of intermediate (G60) (0.45 g, 0.91 mmol),ethyl acrylate (0.6 mL, 0.59 mmol), Pd(OAc)2 (20 mg, 0.091 mmol) andtri-o-tolylphosphine (55 mg, 0.18 mmol) in Et₃N (0.77 mL, 5.46 mmol) andCH₃CN (11 mL) was heated at 120° C. using a single mode microwave(Biotage® initiator60) with a power output ranging from 0 to 400 W for25 min. water and DCM were added and the product was separated on ahydrophobic frit, the solvent was evaporated till dryness. Purificationwas carried out by column chromatography (silica gel, DCM/MeOH: 99/1).The pure fractions were collected and evaporated to dryness. The crudecompound was crystallized from Et₂O, filtered and dried under vacuum toafford 350 mg (75%) of intermediate (G61)

Intermediate (G62): HATU (2.66 g, 7.01 mmol) was added portionwise to amixture of intermediate (E1) (1.88 g, 4.67 mmol),(R)-1,2,3,4-tetrahydro-1-methylisoquinoline (0.82 g, 5.6 mmol) and DIEA(2.45 mL, 14 mmol) in DMF (20 mL) at RT then the mixture was stirredovernight. The mixture was poured out into water, the precipitate wasfiltered off, washed with water and dried (vacuum, 50° C.) to give 2.15g (93%) of intermediate (G62).

Intermediate (G63): HATU (2.32 g, 6.09 mmol) was added portionwise to amixture (thick) of intermediate (E45) (1.8 g, 4.06 mmol) ,(R)-1,2,3,4-tetrahydro-1-methyl-isoquinoline (0.72 g, 4.87 mmol) andDIEA (2.12 mL, 0.74 g/mL, 12.18 mmol) in DMF (20 mL) at RT then themixture was stirred overnight. The mixture was poured slowly out intowater dropwise with stirring (20 min), the precipitate was filtered offand washed with water. The solid was dissolved in DCM, washed with HCl1N and water, dried (MgSO4) and evaporated till dryness. Purification ofthe residue was carried out by flash chromatography over silica gel(Grace Resolve® 40 g, 15-40 μm, DCM/MeOH 97/3). The pure fractions werecollected and evaporated to dryness to afford 1.37 g of intermediate(G63).

Intermediate (G64): A solution of intermediate (G30) (0.32 g, 0.63 mmol)and methyl 5-bromo-3-fluoropicolinate CAS[1211538-72-5](222 mg, 0.9mmol) in a solution of K₂CO₃ ₂M (0.63 mL, 1.264 mmol) and Me-THF (4 mL)was degassed with nitrogen for 10 min. PdCl₂(dppf) DCM (52 mg, 0.06mmol) was added and the resulting mixture was heated at 100° C. using asinglemode microwave (Biotage® initiator60) with a power output rangingfrom 0 to 400 W for 20 min. The mixture was poured out into water andEtOAc, the mixture was filtered through a short pad of Celite®, theorganic layer was separated, washed with brine, dried over MgSO₄ andevaporated till dryness. The residue was purified by columnchromatography (silica gel, Heptane/EtOAc 60/40). The pure fractionswere collected and evaporated to dryness to afford 180 mg (53%) ofintermediate (G64).

The following intermediates were prepared according to the aboveprocedure

Reaction scheme:

Intermediate (G67): A mixture of intermediate (G66) (0.73 g, 1.55 mmol),bis(pinacolato)diboron (0.59 g, 2.32 mmol) and KOAc (0.45 g, 4.6 mmol)in Me-THF (10 mL) was purged with N₂ flow for 10 min then PdCl₂(dppf)DCM(0.13 g, 0.16 mmol) was added. The resulting mixture was heated at 100°C. using a single mode microwave (Biotage® initiator60) with a poweroutput ranging from 0 to 400 W for 20 min. The mixture was poured outinto water and DCM, the organic layer was separated (hydrophobic frit)and evaporated till dryness. Purification was carried out by columnchromatography (silica gel, heptane/EtOAc 60/40). The pure fractionswere collected and evaporated to dryness to afford 620 mg (77%) ofintermediate (G67).

The following intermediates were prepared according to the proceduredescribed for intermediate (G67).

Intermediate (G69): A mixture of intermediate (G20) (1 g, 2 mmol),bis(pinacolato)diboron (0.77 g, 3.04 mmol) and KOAc (0.60 g, 6.08 mmol)in DME (10 mL) was purged with N₂ flow for 10 min then PdCl₂(dppf)DCM(0.166 g, 0.2 mmol) was added. The resulting mixture was heated at 100°C. using a singlemode microwave (Biotage® initiator60) with a poweroutput ranging from 0 to 400 W for 20 min. The mixture was poured outinto water and DCM, the organic layer was separated (hydrophobic frit)and evaporated till dryness. The residue was crystallized from EtOH,filtered off, washed with EtOH and dried (vacuum, 60° C.) to give 1.08g(99%) of intermediate (G69).

The following intermediate was prepared according to the aboveprocedure.

Intermediate (G71): A solution of intermediate (G69) (0.2 g, 0.37 mmol)and 5-bromo-, 2-pyridinecarboxylic acid, methyl ester CAS [29682-15-3](0.12 g, 0.55 mmol) in K₂CO₃ aq. (0.56 mL, 2 M, 1.11 mmol) and DME (2mL) was degassed with nitrogen for 10 min. PdCl₂(dppf)DCM (0.030 g,0.037 mmol) was added and the mixture was heated at 120° C. using asingle mode microwave (Biotage® initiator60) with a power output rangingfrom 0 to 400 W for 20 min. The mixture was poured out into water andDCM/MeOH (9/1), the organic layer was separated (hydrophobic frit) andevaporated till dryness. Purification of the residue was carried out byflash chromatography (silica gel, from Heptane/EtOAc 80/20 toHeptane/EtOAc 60/40). The pure fractions were collected and evaporatedto dryness to afford 0.085 g (42%) of intermediate (G71)

The following intermediate was prepared according to the aboveprocedure.

Reaction scheme:

Intermediate (G73): A solution of intermediate (G20) (0.35 g, 0.71 mmol)and tetrabutylammonium bromide (0.023 g, 0.071 mmol) in DMA (3.5 mL) waspurged with N₂ for 10 min, then N-cyclohexyl-N-methyl-cyclohexanamine(0.226 mL, 1.06 mmol), 2-methyl-2-propenoic acid methyl ester (0.429 mL,3.55 mmol) and dichlorobis[tris(o-tolyl)phosphine]-palladium CAS[40691-33-6] (0.028 g, 0.036 mmol) were added. The mixture was heated at120° C. using a single mode microwave (Biotage® initiator60) with apower output ranging from 0 to 400 W for 20 min. The mixture was pouredout into water, extracted with EtOAc, the organic layer was separated,washed with water then brine, dried over MgSO₄ and evaporated tilldryness (0.74 g).Purification of the residue was carried out by columnchromatography (silica gel, from Heptane/EtOAc 80/20 to Heptane/EtOAc70/30). The pure fractions were collected and evaporated to dryness toafford a mixture of 2 isomers. A purification of this residue wasperformed via achiral SFC (Stationary phase: Lux cellulose® 4 5 μm250*21.2 mm, Mobile phase: 60% CO2, 40% EtOH) to afford 0.19 g (51%) ofthe intermediate (G73).

Intermediate (G76): A mixture of intermediate (E47) (18.7 g, 60.7 mmol),1H-Azepine, hexahydro-2-methyl-, hydrochloride, (2R) CAS [331994-00-4](10.0 g; 66.8 mmol), HATU (30.0 g; 78.9 mmol) and DIEA (32 mL; 186 mmol)in DMF (350 mL) was stirred at RT for 20 hours. The reaction mixture wasdiluted in AcOEt, washed with an aqueous solution of NaHCO3 saturated(twice), brine (3 times), dried over MgSO₄ and evaporated in vacuo togive brownish oil. The brownish oil was purified by columnchromatography (silica gel from heptane/EtOAc 90/10 to 50/50). The purefractions were collected and evaporated to give 21.9 g (99%) ofintermediate (G76) as a yellow gum.

The following intermediates were prepared according to the aboveprocedure.

Intermediate (G77): Under N₂, in a Schlenk tube, bis(pinacolato)diboron(4.12 g, 16.2 mmol) and KOAc (2.66 g, 27.0 mmol) were added to asolution of intermediate (G76) (4.94 g, 13.5 mmol) in 1,4-dioxane (56mL). The solution was purged with nitrogen and charged with PdCl₂(dppf)(1.11 g, 1.35 mmol). The resulting solution was purged again with N₂ andstirred at 100° C. for 4 hours then cooled down. EtOAc was added. Theorganic layer was washed with water and brine (twice), dried over MgSO₄and concentrated to give 8.14 g (quant.) of intermediate (G77) as abrown oil. The product was used in the next step without furtherpurification.

The following intermediates were prepared according to the aboveprocedure.

Reaction scheme:

Intermediate (G78): In a Schlenk tube, to a degassed mixture ofintermediate (G1) (1.0 g; 2.2 mmol), CuI (41 mg; 0.22 mmol) and Et₃N(1.2 mL; 8.8 mmol) in Me-THF (20 mL) was added trimethylsilylacetyleneCAS [1066-54-2](1.2 mL; 8.7 mmol) then PdCl₂(PPh₃)₂ (76 mg; 0.11 mmol)at RT. The resulting mixture was stirred at 100° C. for 16 hours thencooled down. The mixture was filtered over Celite®. Water and EtOAc wereadded to the filtrate. The layers were separated and the aqueous layerwas extracted with EtOAc (once). The combined organic layers were washedwith brine, dried over MgSO₄, filtered and the solvent was removed invacuo. The residue was purified by column chromatography (silica gelfrom heptane/EtOAc 100/0 to 40/60). The pure fractions were collectedand evaporated to give 791 mg (76%) of intermediate (G78).

Reaction scheme:

Intermediate (G79): CO2 was bubbled in a mixture of cesium fluoride (472mg; 3.11 mmol) in DMSO (20 mL) for 5 min then intermediate (G78) (741mg; 1.55 mmol) in DMSO (20 mL) was added. The bubbling of CO₂ wascontinued for 2 hours. CO₂ bubbling was stopped then methyl iodide(1454; 2.33 mmol) was added and the mixture was stirred at RT for 4hours. The mixture was poured into water and the product was extractedwith EtOAc (twice). The combined organic layers were washed with brine,dried over MgSO₄, filtered and the solvent was removed in vacuum. Theresidue was purified by column chromatography (silica gel, fromheptane/EtOAc 100/0 to 60/40). The good fractions were collected andevaporated to give 449 mg (62%) of intermediate (G79).

Reaction scheme:

Intermediate (G80): In a sealed tube, a solution of intermediate (G77)(490 mg; 0.81 mmol; 68%), intermediate (R1) (232 mg; 0.808 mmol) andK₃PO₄ (515 mg; 2.42 mmol) in dioxane (9.1 mL) and H₂O (1.4 mL) waspurged with Nz. PdCl₂(dtbpf) (53 mg; 81 μmol) was added, the mixture waspurged again with Nz and heated at 80° C. using one single modemicrowave (Biotage® Initiator EXP 60) with a power output ranging from 0to 400 W for 30 min. The mixture was poured into DCM, washed with water(twice), brine, dried over MgSO₄, filtered and evaporated in vacuum. Theresidue was purified by column chromatography (silica gel, fromheptane/EtOAc 100/0 to 60/40). The pure fractions were collected andevaporated to give 0.21 g of a mixture of 2 diastereomers. The mixtureof 2 diastereomers was purified by chiral SFC (Stationary phase:Chiralcel® OJ-H 5 μm 250×20 mm, Mobile phase: 90% CO₂, 10% MeOH). Thepure fractions were collected to give 79 mg of intermediate (G80) (R*,R*) (first diastereomer) and 87 mg of intermediate (G80′) (S*, S*)(second diastereomer).

The following intermediates were prepared according to the aboveprocedure:

Intermediate (G81): In a sealed tube, a solution of intermediate (G77)(444 mg; 1.08 mmol), ethyl(E)-3-(3-bromo-2-fluoro-phenyl)prop-2-enoate(245 mg; 0.897 mmol) and K₃PO₄ (571 mg; 2.69 mmol) in 1,4-dioxane (8.9mL) and H₂O (1.3 mL) was purged with N₂. PdCl₂(dtbpf) (58 mg; 90 μmol)was added, the mixture was purged again with N₂ and heated at 80° C.using one single mode microwave (Biotage® Initiator EXP 60) with a poweroutput ranging from 0 to 400 W for 30 min. The mixture was poured intoDCM, washed with water (twice), brine, dried over MgSO₄, filtered andevaporated in vacuum to give a brown solid which was purified by columnchromatography (silica gel, from DCM/EtOAc 100/0 to 95/5). The purefractions were collected and evaporated to give 223 mg (52%) ofintermediate (G81).

The following intermediates were prepared according to the aboveprocedure:

Reaction scheme

Intermediate (G82): DIEA (0.250 mL; 1.44 mmol) then HATU (0.328 g; 0.863mmol) were added to a mixture of intermediate E49 (0.300 g; 0.719 mmol)and, 2,3,4,5-tetrahydro-1-methyl-1H-2-benzazepine CAS [1521361-53-4](0.139 g, 0.863 mmol) in DMF (3 mL) and the resulting mixture wasstirred at RT for 15 hours, then added dropwise to stirred water (20mL). The resulting precipitate was collected by filtration on a glassfrit, then taken in DCM (50 mL), washed with HCl 1M (2×10 mL) and brine(10 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude brownish solid was purified by column chromatography(silica gel: from DCM/EtOAc 100/0 to 99/1 to 98/2). The pure fractionswere collected and evaporated to give 250 mg (63%) of intermediate (G82)as a yellowish solid.

Reaction scheme:

Intermediate (G89): To a degassed mixture of intermediate (G1) (473 mg,1.03 mmol), methyl azetidine-3-carboxylate, hydrochloride (188 mg, 1.24mmol) and Cs₂CO₃ (1.0 g, 3.1 mmol) in 1,4-dioxane (19 mL) was addedsuccessively X-Phos (44 mg; 93 μmol) then Pd₂(dba)₃ (38 mg; 41 μmol) atRT. The resulting mixture was stirred at 100° C. for 4 hours then cooleddown. Water was added and the mixture was extracted with EtOAc (twice).The combined organic layers were washed with brine, dried over MgSO₄,filtered and the solvent was removed in vacuum to give 0.51 g of crudeproduct which was purified by column chromatography (silica gel, fromheptane/EtOAc 80/20 to 40/60). The pure fractions were collected andevaporated to give 0.407g (80%) of intermediate (Q1).

The following intermediates were prepared according to the aboveprocedure.

A mixture of intermediate El (0.500 g, 1.09 mmol), [1068583-95-8] (0.266g, 1.31 mmol), ^(t)BuONa (0.314 g, 3.27 mmol), Pd₂dba₃ (0.0498 g, 0.0544mmol) and Binap (0.0678 g, 0.109 mmol) in toluene (10 mL) was stirredunder pW irradiation (Biotage®) at 90° C. for 0.5 h. The reactionmixture was diluted with EtOAc (100 mL), washed with water (100 mL) andbrine (100 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by preparative LC over silicagel (irregular SiOH, 40-63 μm, Fluka®, mobile phase gradient: fromDCM/EtOAc 100/0 to 95/5). The product fractions were collected and thesolvent was evaporated. The solid was purified again by preparative LC(irregular SiOH, 40-63 μm, Fluka®, mobile phase gradient: fromcyclohexane/EtOAc 80/20 to 70/30). The product fractions were collectedand the solvent was evaporated to give 0.245 2 (21%) of esterintermediate as a yellowish solid.

Reaction scheme:

Intermediate (G90): In a sealed tube, a solution of intermediate (G77)(738 mg; 1.09 mmol), intermediate (S4) (388 mg; 1.22 mmol) and K₃PO₄(775 mg; 3.65 mmol) in 1,4-dioxane (13 mL) and water (2 mL) was purgedwith N₂. PdCl₂(dtbpf) (80 mg; 123 μmol) was added, the mixture waspurged again with N₂ and heated at 80° C. using one single modemicrowave (Biotage® Initiator EXP 60) with a power output ranging from 0to 400 W for 30 minutes. EtOAc and water were added. The layers wereseparated and the organic layer was washed with brine, dried on MgSO₄,filtered and concentrated to give crude product which was purified bycolumn chromatography (silica gel, from heptane/EtOAc 80/20 to 40/60).The pure fractions were collected and evaporated to give 412 mg (74%) ofintermediate (G90) as a beige solid.

The following intermediates were prepared according to the aboveprocedure:

Reaction scheme:

Intermediate (G91): A solution of intermediate (G30) (400 mg; 0.79mmol), 4-((trifluoro-methanesulfonyl)oxy)-3-cyclohexene-1-carboxylicacid ethyl ester (239 mg; 0.79 mmol) and K₃PO₄ (503 mg; 2.37 mmol) in1,4-dioxane (11 mL) and H₂O (3.3 mL) was purged by N₂ bubbling for 10minutes before the addition of PdCl₂(dtbpf) (51 mg; 78.9 μmol). Theresulting mixture was purged by N₂ bubbling, then heated at 80° C. usingone single mode microwave (Biotage® Initiator EXP 60) with a poweroutput ranging from 0 to 400 W for 30 minutes. The crude was poured intoDCM, washed with water (twice), brine, dried over MgSO₄, filtered andevaporated in vacuum. The residue was purified by column chromatography(silica gel, from DCM/EtOAc 100:0 to 90:10). The fractions containingproduct were combined and the solvent was removed to give 252 mg (60%)of intermediate (G91) as a brown oil and as a mixture of 2diastereomers.

Reaction scheme:

Intermediate (G99): To a mixture of intermediate El (500 mg; 1.24 mmol),t-butyl carbazate (328 mg; 2.49 mmol) and DIEA (0.64 mL; 3.7 mmol) inDMF (20 mL) was added COMU (798 mg; 1.86 mmol) and the resulting mixturewas stirred at rt with mechanical stirring for 16 h. Water was added andthe product was extracted with EtOAc (twice). The combined organiclayers were washed with brine, dried over MgSO₄, filtered and thesolvent was removed in vacuo. The residue was purified by preparative LC(regular SiOH, 30 μm, 40 g interchim®, liquid loading (DCM/heptane),mobile phase gradient: from heptane/EtOAc 100/0 to 40/60) to give 339 mg(57%) of intermediate (G99).

The following intermediates were prepared using analogous procedures :

Intermediate (G100): A mixture of intermediate (G99) (0.72 g; 1.51mmol), 1,5-dibromopentane (0.22 mL; 1.58 mmol) and Cs2CO3 (490 mg; 1.51mmol) in MeCN (36 mL) was stirred at 70° C. for 16 h. An extra amount ofCs₂CO₃ (200 mg; 0.614 mmol) and 1,5-dibromopentane (50 μL; 0.37 mmol)were added and the mixture was stirred at 90° C. for 2 h. Water wasadded and the mixture was extracted with DCM (twice). The combinedorganic layers were washed with brine, dried over MgSO₄, filtered andthe solvent was removed in vacuo. The residue was purified bypreparative LC (regular SiOH, 30 μm, 120 g interchim®, liquid loading(DCM), mobile phase gradient: from heptane/EtOAc 100/0 to 40/60) to give0.44 g (53%) of intermediate (G100).

The following intermediates were prepared using analogous procedures :

Intermediate (G101): A mixture of intermediate (G100) (0.71 g; 1.3 mmol)and TFA (3.0 mL; 39 mmol) in DCM (15 mL) was stirred at rt for 16 h. Anaqueous solution of NaHCO₃ (sat) and DCM were carrefully added and thelayers were separated. The aqueous layer was extracted with DCM (once).The combined organic layers were washed with brine, dried over MgSO₄,filtered and the solvent was removed in vacuo to give 0.52 g (90%) ofintermediate (G101).

The following intermediates were prepared using analogous procedures :

Intermediate (G102): To a mixture of intermediate (G101) (638 mg; 1.43mmol) and formaldehyde 37% in water (0.215 mL; 2.86 mmol) in MeOH (14mL) and AcOH (1.4 mL) was added NaBH₃CN 1M in THF (1.7 mL; 1.7 mmol) atrt. The resulting mixture was stirred at 40° C. for 2 h. DCM and waterwere added and the layers were separated. The aqueous layer wasextracted with DCM (once). The organic layers were washed with anaqueous solution of HCl (1N), then brine, dried over MgSO₄, filtered andthe solvent was removed in vacuo. The residue was taken-up with MeCN,the precipitate was filtered off and dried over glass frit to give 280mg of intermediate (G102). The filtrate was evaporated and purified bypreparative LC (regular SiOH, 30 μm, 25 g intechim®, liquid loading(DCM), mobile phase gradient: from heptane/EtOAc 100/0 to 40/60) to give99 mg (57%) of intermediate (G102).

The following intermediates were prepared using analogous procedures :

Intermediate (G103): In a Schlenk, a mixture of intermediate (G102)(0.380 g; 0.825 mmol), B₂pin₂ (0.314 g; 1.24 mmol) and KOAc (243 mg;2.48 mmol) in dioxane (10 mL) was purged by N₂ bubbling for 10 minbefore the addition of PdCl₂dppf (68 mg; 83 μmol). The resulting mixturewas heated at 100° C. for 2 h then at rt for 18 h. The reaction mixturewas filtered over celite, the celite was rinsed with EtOAc. Water wasadded to the filtrate, the aqueous layer was extracted with EtOAc(twice). The combined organic layers were dried over MgSO₄, filtered andconcentrated in vacuo to give 610 mg (quant, purity 69%) of intermediate(G103).

The following intermediates were prepared using analogous procedures :

Intermediate (G104)

In a sealed tube, a solution of intermediate (G103) (765 mg; 1.04 mmol,purity 69%), ethyl 6-chloronicotinate (232 mg; 1.25 mmol) and K₃PO₄ (662mg; 3.12 mmol) in dioxane (10 mL) and H₂O (2 mL) was purged with N₂.Pd118 (54 mg; 83 μmol) was added, the mixture was purged again with N₂and heated at 100° C. for 18 hours. The reaction mixture were filteredover celite, celite was rinsed with EtOAc and water. Brine was added tothe filtrate. The aqueous layer was extracted with EtOAc, the combinedorganic layers were dried over MgSO₄, filtered and evaporated in vacuo.The residue was purified by preparative LC (irregular SiOH, 15-40 μm, 40g Grace Resolve , liquid loading (DCM), mobile phase: heptane/EtOAc80/20) give 267 mg (48%) of intermediate (G104) as a solid.

The following intermediates was prepared according to intermediate(G104):

Reaction scheme:

Intermediate (G106): A screw-cap tube was charged with intermediate (G1)(0.300 g, 0.653 mmol), Ethyl 4-pyrazolecarboxylate (0.100 g, 0.718mmol), K₃PO₄ (0.291 g, 1.371 mmol) and Cul (0.006 g, 0.033 mmol). Thetube was capped with a septum and purged with argon.N,N′dimethylethylenediamine (0.014 mL, 0.131 mmol) and toluene (1 ml)were added via a syringe through the septum. The reaction flask wassealed and placed in a pre-heated oil bath at 90° C. and stirred for 24h. The reaction mixture was cooled to rt and 10 mL of EtOAc were added.The organic layer was washed successively with 5 mL of water and 5 mL ofbrine, dried with Na₂SO₄, filtered, concentrated in vacuo and purifiedby Preparative LC (irregular SiOH, 40-63 μm, liquid loading (DCM),mobile phase: DCM/EtOAc, 90/10) to give 317 mg (94%) of intermediate(G106).

The following compounds were prepared according to the above procedure.

Intermediate (G117): A screw cap tube was charged with intermediate(G88) (0.32 g, 0.659 mmol), ethyl /H-pyrazole-4-carboxylate (0.277 g,1.978 mmol), K₂CO₃ (0.273 g, 1.978 mmol), Cul (0.0505 g, 0.264 mmol) andN,N-dimethyl-1,2-cyclohexanediamine (0.0421 mL, 0.264 mmol) and purgewith N2. The tube was capped with a septum then purged again withnitrogen. DMF was added and the mixture was heated at 110° C. for 18 h.The reaction mixture was poured out into water, extracted with EtOAc,the organic layer was washed with water then brine, dried (MgSO₄) andevaporated till dryness. Purification of the residue was carried out byflash chromatography over silica gel (cartridge 24 g, 15-40 μm,Heptane/EtOAc 80/20 to Heptane/EtOAc 70/30). The pure fractions werecollected and evaporated to dryness to give 0.22 g (61%) of intermediate(G117).

intermediate (G117)

The following intermediates were prepared according to the aboveprocedure:

Reaction scheme:

Pd/C (10%) (40 mg; 37.5 μmol) was added to a degassed solution ofintermediate (G91) (200 mg; 0.375 mmol) in MeOH (3 mL). The resultingmixture was hydrogenated at rt under 1 bar overnight. The mixture wasfiltered through a pad of Celite®, the filtrate was concentrated untildryness to give 199 mg of intermediate (G119) (99%) as a colorless oil.

Intermediate (G140):

A solution of CataCXium PtBR (19.9 mg, 0.026 mmol) and Pd₂dba₃ (7.5 mg,0.022 mmol) in 1,4-dioxane was degassed under N₂ for 20 min. A solutionof intermediate (G1) (200 mg, 0.435),3-methyl-pyrrolidine-3-methylcarboxylate (67.5 mg, 0.471 mmol) and K₃PO₄(277.2 mg, 1.306 mmol) in 1,4-dioxane (9.2 mL) and water (0.15 mL) wasdegassed under N₂ and added to the previous premix. The mixture wasdegassed for 5 additional minutes and then heated at 110° C. for 16 h.The mixture was partitioned between water and DCM and the organic layerwas separated through a hydrophobic frit and concentrated under reducedpressure. Purification was carried out by flash chromatography oversilica gel (15-40 μm, Grace® 12 g, Hept/EtOAc, 70/30) yielding 0.141 g(56%) of intermediate (G140) as a yellow oil.

The following intermediates were prepared according to the aboveprocedure:

Intermediate (G142):

A solution of intermediate (G141) (700 mg, 0.526 mmol), APTS (905.1 mg,5.26 mmol), pyridine (415.7 μL, 5.26 mmol) and TBAF (1M in THF) (5.25mL, 5.26 mmol) in THF (5.05 mL) was stirred at room temperature for 63 hthen quenched with NaHCO₃ 10% and diluted with DCM. The layers wereseparated and the organic layer was concentrated under reduced pressure.Purification was carried out by flash chromatography (silica gel,Heptane/EtOAc, 70/30) yielding 0.182 g (63%) of intermediate (G142) as ayellow oil.

Intermediate (G144):

To a degassed mixture of intermediate (G1) (0.35 g, 0.76 mmol), ethyl6-(methylamino)-pyridine-3-carboxylate (0.16 g, 0.91 mmol) and Cs₂CO₃(0.74 g, 2.29 mmol) in 1,4-dioxane (14 mL) was added successively XPhos(0.028 g, 0.03 mmol) then Pd₂dba₃ (0.033 g, 0.069 mmol) at roomtemperature. The resulting mixture was stirred at 100° C. for 16 h. Thesolution was cooled down to room temperature and water was added. Themixture was extracted with EtOAc (twice). The combined organic layerswere washed with brine, dried over MgSO₄, filtered and the solvent wasremoved in vacuo to give yellow oil. Purification was carried out byflash chromatography over silica gel (GraceResolv®, 40 g, 15-35 μM,Heptane/EtOAc 90/10 to 70/30). Pure fractions were collected andevaporated to afford 0.483 g, as pale yellow oil. A second purificationwas carried out by flash chromatography over silica gel (GraceResolv®,40 g, 15-35 μM, Heptane/EtOAc 80/20 to 70/30). Pure fractions werecollected and evaporated to afford 0.372 g (87%) of intermediate (G144)as a colorless oil. Used as such for next step.

Intermediates (G145) and (G146):

To a degassed mixture of intermediate (G1) (0.38 g, 0.82 mmol),intermediate (U4) (0.22 g, 0.98 mmol) and Cs₂CO₃ (0.8 g, 2.45 mmol) in1,4-dioxane (15 mL) was added successively XPhos (0.03 g, 0.033 mmol)then Pd₂dba₃ (0.035 g, 0.073 mmol) at room temperature. The resultingmixture was stirred at 100° C. for 16 h. The solution was cooled down toroom temperature and water was added. The mixture was extracted withEtOAc (twice). The combined organic layers were washed with brine, driedover MgSO₄, filtered and the solvent was removed in vacuum to give 0.445g of a crude mixture. Purification was carried out by flashchromatography over silica gel (GraceResolv®, 15-35 μM, 40 g,Heptane/EtOAc from 85/15 to 70/30). Pure fractions were collected andevaporated to give 0.163 g of a pale yellow foam. A second purificationwas performed via achiral SFC (Stationary phase: CHIRALCEL® OJ-H 5 μm250'20 mm, Mobile phase: 75% CO₂, 25% MeOH). Pure fractions werecollected and evaporated to give 0.126 g of intermediate (G145) and0.270 g of intermediate (G146).

Intermediate (G148):

A mixture of intermediate (G147) (2.3 g, 5.1 mmol), ethyl/H-pyrazole-4-carboxylate CAS [37622-90-5] (2.1 g, 15.4 mmol), K₂CO₃(2.1 g, 15.4 mmol), CuI (0.98 g, 5.1 mmol) and N,N′-DMEDA (0.8 mL, 5.1mmol) was purged with N₂. DMF (20 mL) was added and the mixture washeated at 100° C. overnight. The reaction mixture was poured out intowater, extracted with EtOAc, the mixture was filtered through a shortpad of Celite® and the organic layer was separated, washed with waterthen brine, dried (MgSO₄) and evaporated till dryness. Purification wascarried out by flash chromatography over silica gel (cartridge 120 g,15-40 μm, DCM to DCM/MeOH 95/5). The pure fractions were collected andevaporated to dryness to afford lg (38%) of intermediate (G148).

Intermediate (G151): A mixture of intermediate (E55) (1.58 g; 4.94mmol), (1R)-1,2,3,4-tetrahydro-1-methyl-isoquinoline (872 mg; 5.92mmol), HATU (2.44 g; 6.41 mmol) and DIEA (2.6 mL; 15.1 mmol) in DMF (29mL) was stirred at rt for 20 hours. The reaction mixture was dilutedwith ethyl acetate, washed with a sat. aq. solution of NaHCO₃ (twice),brine (3 times), dried over MgSO₄ and evaporated till dryness undervacuum. The compound was purified by preparative LC (irregular SiOH15-40 μm, 80 g Grace® Resolv, liquid loading (DCM), mobile phasegradient: from heptane 90%, EtOAc 10% to Heptane 50%, EtOAc 50%) to give1.84 g of intermediate (G151) as a white foam (91%).

Intermediate (G152): Under N₂, in a schlenk tube, B₂pin₂ (904 mg; 3.56mmol) and KOAc (582 mg; 5.93 mmol) were added to a solution ofintermediate (G151) (1.22 g; 2.97 mmol) in 1,4-dioxane (20 mL). Thesolution was purged with nitrogen and charged with PdCl₂(dppf) (243 mg;0.297 mmol). The resulting solution was purged again with nitrogen andstirred to 100° C. for 4 hours. EtOAc was added. The organic layer waswashed with water and brine (twice), dried over MgSO₄ and concentratedtill dryness to give 2.2 g of intermediate (G152) as brown oil (theproduct was engaged without further purification in the following step).

Intermediate (G153):

In a sealed tube, a solution of intermediate (G152) (0.75 g; 0.982 mmol;60% purity), intermediate (R10) (468 mg; 1.18 mmol) and K₃PO₄ (625 mg;2.95 mmol) in dioxane (13.9 mL) and H₂O (2.1 mL) was purged with Nz.PdCl₂(dtbpf) (64 mg; 0.098 mmol) was added, the mixture was purged againwith Nz and heated at 80° C. using a single mode microwave (Biotage®Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min[fixed hold time]. EtOAc and water were added. The layers were separatedand the organic layer was washed with brine (twice), dried on MgSO₄,filtered, concentrated and purified by preparative LC (irregular SiOH,15-40 μm, 50 g Grace® Resolv, liquid loading (DCM), mobile phasegradient: from Heptane/EtOAc 90/10 to 70/30) to give 1.02 g (80%) ofintermediate (G153) as a pale yellowish solid.

The following intermediates were prepared using analogous procedures :

Intermediate (G155): A solution of intermediate G77 (570 mg; 1.38 mmol),7-bromo-8-fluoro-2(1H)-Quinolinone (335 mg; 1.38 mmol) and K₃PO₄ (880mg; 4.15 mmol) in dioxane (15 mL) and H₂O (3 mL) was purged by N₂bubbling for 10 min before the addition of PdCl₂dtbpf (270 mg; 0.415mmol). The resulting mixture was purged by N₂ bubbling then heated at80° C. using a single mode microwave (Biotage® Initiator EXP 60) with apower output ranging from 0 to 400 W for 30 min [fixed hold time]. Anadditional amount of intermediate G77 (200 mg; 0.485 mmol) was added andthe mixture was degassed by N₂ bubbling for 10 min before the additionof additional PdCl₂dtbpf (100 mg; 0.153 mmol). The mixture was degassedagain by N₂ bubbling for 5 min then heated at 80° C. using a single modemicrowave (Biotage® Initiator EXP 60) with a power output ranging from 0to 400 W for 30 min [fixed hold time]. The crude was poured into DCM,washed with water (twice), brine, dried over MgSO₄, filtered andevaporated in vacuum. The crude was taken-up in MeCN, the solid wasfiltered off and dried under vacuum to give 387 mg (46%) of intermediate(G155) as an off-white solid.

Intermediate (G156): NaH 60% dispersion in mineral oil (23 mg; 0.908mmol) was added to a solution of intermediate (G155) (387 mg; 0.865mmol) in dry DMF (7 mL) at 0° C. The resulting mixture was stirred at 0°C. for 30 min before the addition of PhNTf₂ (324 mg; 0.908 mmol). Themixture was allowed to warm to rt then stirred at rt overnight. Waterwas added and the mixture was extrated with DCM (twice). The combinedorganic layers were washed with brine (twice), dried over MgSO₄,filtered and concentrated in vacuum to give yellow oil which wasdissolved in dry DMF (7 mL). The mixture was cooled to 0° C. before theaddition of additional NaH (23 mg; 0.908 mmol). The resulting mixturewas stirred at 0° C. for 30 min then additional PhNTf₂ (324 mg; 0.908mmol) was added and the mixture was allowed to warm to rt and stirred atrt for 4 h. Water was added and the mixture was extracted with EtOAc(twice). The combined organic layers were washed with brine (3 times),dried over MgSO₄, filtered and concentrated in vacuum to give 662 mg(Quant, purity 75%) of intermediate (G156) as a brown solid.

Intermediate (G160): A mixture of crude intermediate (G159) (0.881 g,1.50 mmol), 4-bromo-3-fluoro-2-hydroxybenzaldehyde (0.493 g, 2.25 mmol),K₃PO₄ (0.955 g, 4.50 mmol) and PdCl2(dtbpf) (0.0489 g, 0.0750 mmol) in amixture of dioxane/H₂O (8:2) (10 ml) was stirred at 100° C. for 1 h,then allowed to cool down to rt, diluted with ethyl acetate (50 ml),washed with brine (2×50 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude brown gum was purified bycolumn chromatography (silica gel, mobile phase DCM/EtOAc 100/0 to95/5). The pure fractions were collected and the solvent was evaporatedto yield 0.210 g of intermediate (G160) as a beige sticky solid.

The following intermediates were prepared using analogous procedures :

Intermediate (G168): A mixture of intermediate (G160) (0.210 g, 0.466mmol), diethylmalonate (0.106 ml, 0.699 mmol), piperidine (0.0046 mL,0.0466 mmol) and AcOH (0.0027 mL, 0.0466 mmol) in EtOH (3 mL) wasstirred at reflux for 16 h, allowed to cool down to rt and diluted withwater (15 mL). The precipitate was collected by filtration on a glassfrit, washed with water (2×10 mL), taken up in DCM (25 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudematerial was purified by column chromatography (silica gel, mobile phaseDCM/EtOAc 100/0 to 95/5). The pure fractions were collected and thesolvent was evaporated under reduced pressure to yield 0.176 g (69%) ofintermediate (G168) as a yellowish solid.

The following intermediate was prepared using analogous procedures :

Intermediate (G162): HCl 4M in dioxane (40.0 mL, 159 mmol) was added toa solution of intermediate (G161) (3.70 g, 7.95 mmol) in dioxane (40.0ml) and H₂O (0.3 mL, 15.9 mmol) at rt. The reaction mixture was stirredat rt overnight. Reaction mixture was concentrated to dryness andpurified by preparative LC (Regular SiO₂, 50 μm, Interchim® 120 g,mobile phase gradient: from DCM/MeOH 98/2 to 50/50) to give 2.80 g (82%)of intermediate (G162) as a yellow powder.

Intermediate (G163): DEAD 40% in toluene (2.30 mL, 5.08 mmol) was addedto a solution of intermediate (G162) (1.80 g, 4.23 mmol), PPh₃ (1.33 g,5.08 mmol) and Ziram® (1.55 g, 5.08 mmol) in toluene (21 mL) at rt. Thereaction mixture was stirred at rt for 16 h and filtered. The cake waswashed with DCM and the filtrate was concentrated under reduce pressure.The residue was purified by preparative LC (Regular C18, 50 μm,Interchim® 175 g, mobile phase gradient: from MeCN/H₂O 02/98 to 100/0).The desired fraction was collected and evaporated in vacuum to yield0.690 g (41%) of intermediate (G163) as a beige powder.

Intermediate (G164): Intermediate (G163) (0.240 g, 0.590 mmol) and K₃PO₄(0.375 g, 1.780 mmol) were added to a solution of intermediate (R19)(0.570 g, 1.78 mmol) in dioxane (3 ml) and H₂O (0.4 mL) at rt. Themixture was purged (twice) with argon and PdCl₂dtbpf (0.038 g, 0.059mmol) was added. The mixture was purged again (twice) with argon andstirred at 100° C. for 2 h. The mixture was purged (twice) with argonand an additional amount of PdCl₂dtbpf (0.038 g, 0.059 mmol) was added.The mixture was purged again (twice) with argon and stirred at 100° C.for 2 h. The mixture was purged (twice) with argon and an additionalamount of PdCl₂dtbpf (0.038 g, 0.059 mmol) was added. The mixture waspurged again (twice) with argon and stirred at 100° C. for 2 h. Thereaction mixture was quenched with water and extracted with DCM (50 mL).The organic layer was dried (Na₂SO₄), filtered and concentrated underreduced pressure. The residue was purified by preparative LC (RegularSiOH, 50 μm, Interchim® 40 g, mobile phase gradient: fromEtOAc/cyclohexane 10/90 to 50/50). The desired fraction was collectedand evaporated in vacuo to give an orange oil which was triturated inpentane several times to yield 0.112 g (36%) of intermediate (G164) as abeige powder.

The following intermediates were prepared according to intermediate(G164)

Intermediate (G173):

A solution of intermediate (G122) (825 mg; 0.285 mmol), intermediate(R10) (136 mg; 0.342 mmol) and K₃PO₄ (182 mg; 0.855 mmol) in 1,4-dioxane(3.9 mL) and H₂O (1.1 mL) was purged with N₂ for 10 min before theaddition of PdCl₂(dtbpf) (19 mg; 28.5 μmol). The resulting mixture waspurged with N₂ then heated at 80° C. using a single mode microwave(Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 Wfor 30 min [fixed hold time]. The mixture was poured into CH₂Cl₂, washedwith water (twice), brine, dried over MgSO₄, filtered and evaporated invacuum. The compound was purified by preparative LC (Regular SiOH 30 μm,25 g Interchim®, liquid loading (DCM), mobile phase gradient: fromheptane/EtOAc 90:10 to 60:40). The fractions containing product werecombined and the solvent was removed in vacuo to give 135 mg (73%) ofintermediate (G173).

Intermediate (G220): DIEA (0.65 mL, 3.62 mmol) and HATU (0.55 g, 1.45mmol) were added to a mixture of intermediate (E46) (0.50 g, 1.21 mmol)and (1R)-1,2,3,4-tetrahydro-1-methyl-isoquinoline (0.20 g, 1.33 mmol) inDMF (8 mL). The resulting mixture was stirred at rt for 16 hours. Thereaction mixture was poured into water (80 mL) dropwise with stirring(20 min). The precipitate was centrifuged. The solid was dissolved inDCM (10 mL), washed with 10 mL of 1N aqueous HCl and 10 mL of H₂O. Theorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuoto afford 0.720 g (quant.) of intermediate (G220) as a brownish gum.

Intermediate (G223): PdCl₂(15 mg; 4.48 mmol) was added to a degassedsolution of intermediate (G1) (1.2 g; 2.61 mmol), potassiumvinyltrifluoroborate (600 mg; 4.48 mmol), Cs₂CO₃ (3.72 g; 11.4 mmol) andPPh₃(60 mg; 0.229 mmol) in THF (30 mL) and H₂O (3 mL). The mixture wasstirred at reflux for 7 hours. The mixture was extracted with DCM andwater. The organic layer was washed with brine, dried over MgSO₄,filtered, evaporated and purified by preparative LC (irregular SiOH15-40 μm, 120 g Grace® Resolv, mobile phase gradient : fromheptane/EtOAc 100/0 to 50/50 to give 858 mg (72%) of intermediate(G223).

Intermediate (G224): Under N2, a solution of ethyl diazoacetate (411 μL,3.32 mmol) in DCM (20 mL) was added slowly over 40 min to a solution ofintermediate (G223) (500 mg; 1.11 mmol) and Rh(OAc)₂ (15 mg; 67.9 μmol)in DCM (10 mL). The mixture was stirred at rt for 3 hours. An additionalamount of ethyl diazoacetate (411 μL, 3.32 mmol) in DCM (20 mL) wasadded slowly over 40 min and the mixture was stirred at rt for18hours.The mixture was evaporated and purified by preparative LC(irregular SiOH 15-40 μm, 120 g Grace® Resolv, liquid loading (DCM),mobile phase gradient: from heptane/EtOAc from 100:0 to 70:30 in 10 CV)to give 85 mg (15%) of intermediate(G224) as a yellow solid.

Intermediate (G258): HATU (1.6 g; 4.21 mmol) was added to a suspensionof intermediate (E47) (1 g; 3.24 mmol), intermediate (F22) (0.68 g; 3.57mmol) and DIEA (1.7 mL; 9.95 mmol) in DMF (20 mL) (the reaction mixtureturn on yellow and clearless after a few minutes). The reaction mixturewas stirred at rt for 16 h. The reaction mixture was diluted in ethylacetate, washed with water, brine (3 times), dried over MgSO₄ andevaporated in vacuum. The crude mixture was purified by preparative LC(Regular SiOH 15-30 μm, 40 g Interchim®, dry loading (on SiOH), mobilephase gradient: from heptane/EtOAc; 90/10 to 50/50) to give 1.31 g(Quantitative yield) of intermediate (G258) as a white foam.

Intermediate (G268): Under N₂, in a sealed tube, Bispin (985 mg; 3.88mmol) and KOAc (634 mg; 6.46 mmol) were added to a solution ofintermediate (G258) (1.31 g; 3.23 mmol) in 1,4-dioxane (15 mL). Thesolution was purged with nitrogen and charged with PdCl₂(dppODCM (265mg; 323 μmol). The resulting solution was purged again with nitrogen andstirred at 100° C. for 4 h. EtOAc was added. The organic layer waswashed with water and brine (twice), dried over MgSO₄ and concentratedto give 2.37 g (Quant.) of intermediate (G268).The compound was engagedwithout further purification in the following step.

Intermediate (G279): In a sealed tube, a solution of intermediate (G268)(500 mg; 0.68 mmol; 62%), intermediate (R10) (286 mg; 0.72 mmol) andK₃PO₄ (436 mg; 2.06 mmol) in 1,4-dioxane (10.5 mL) and H₂O (2.5 mL) waspurged with Nz. PdCl₂(dtbpf) (45 mg; 69 μmol) was added, the mixture waspurged again with N₂ and heated at 80° C. using one single modemicrowave (Biotage® Initiator EXP 60) with a power output ranging from 0to 400 W for 30 min [fixed hold time]. EtOAc and water were added. Thelayers were separated and the organic layer was washed with brine, driedon MgSO₄, filtered and evaporated till dryness. The crude mixture waspurified by preparative LC (Regular SiOH, 15-30 μm, 25 g Interchim®, dryloading (on SiOH), mobile phase gradient: from heptane/EtOAc 100/0 to50/50) to give 293 mg (67%) of intermediate (G279) as a white foam.

Intermediate (G286): In a Schlenk tube, a solution of intermediate(G272) (1.79 g; 2.35 mmol; 75% purity), ethyl-6-chloronicotinate (522mg; 2.81 mmol) and K₃PO₄ (1.49 g; 7.04 mmol) in dioxane (32 mL) and H₂O(6 mL) was purged with N₂. PdCl₂dtbpf (153 mg; 0.234 mmol) was added,the mixture was purged again with N₂ and heated at 80° C. for 4 h. EtOAcand water were added. The layers were separated and the organic layerwas washed with brine (3 times), dried on MgSO₄, filtered, concentratedand purified by preparative LC (Regular SiOH, 30 μm, 80 g Grace® Resolv,liquid loading (DCM), mobile phase gradient: from Heptane/EtOAc 90/10 to60/40) to give 913 mg (65%) of intermediate (G286) as a yellowish solid.

The following intermediate was prepared according to the aboveprocedure.

Intermediate (G220): DIEA (0.65 mL, 3.62 mmol) and HATU (0.55 g, 1.45mmol) were added to a mixture of intermediate (E46) (0.50 g, 1.21 mmol)and (1R)-1,2,3,4-tetrahydro-1-methyl-isoquinoline (0.20 g, 1.33 mmol) inDMF (8 mL). The resulting mixture was stirred at rt for 16 hours. Thereaction mixture was poured into water (80 mL) dropwise with stirring(20 min). The precipitate was centrifuged. The solid was dissolved inDCM (10 mL), washed with 10 mL of 1N aqueous HCl and 10 mL of H₂O. Theorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuoto afford 0.720 g (quant.) of intermediate (G220) as a brownish gum.

Intermediate (G288):A screw-cap tube was charged with intermediate(G220) (0.720 g, 1.207 mmol maximal), Ethyl(3S)-pyrrolidine-3-carboxylate hydrochloride (0.260 g, 1.448 mmol),cesium carbonate (0.590 g, 1.810 mmol), Pd₂dba₃ (0.030 g, 0.030 mmol)and Xantphos (0.035 g, 0.060 mmol). The tube was capped with a septumand purged with argon. Dioxane (5 mL) was added via a syringe throughthe septum. The reaction flask was sealed and placed in a pre-heated oilbath at 100° C. and stirred for 24 h. The reaction mixture was cooled tort and 10 mL of AcOEt were added. The organic layer was washedsuccessively with 5 mL of water and 5 mL of brine, dried with Na₂SO₄,filtered and concentrated in vacuo to give yellowish oil. The crude waspurified by preparative LC (silica gel, mobile phase: gradient fromDCM/EtOAc 100/00 to 90/10) to give 0.189 g (28%) of intermediate (G288)as yellow solid.

Intermediate (G298): A mixture of intermediate (G274) (370 mg; 0.700mmol) and LiOHH2O (25 mg; 1.1 mmol) in THF (7 mL) and H₂O (3 mL) wasstirred at rt for 1 h. Water and EtOAc were added and the layers wereseparated. The aqueous layer was extracted with EtOAc (once). Thecombined organic layers were washed with brine, dried over MgSO₄,filtered and the solvent was removed in vacuo to give 345 mg ofintermediate (G298).

Intermediates (G299) and (G300): A purification of 0.682 g ofintermediate (G143) was performed via chiral SFC (Stationary phase:Whelk® O1 (S,S) 5 um 250*21.1 mm, Mobile phase: 45% CO₂, 55% MeOH). Purefractions were collected and evaporated to give 0.26 g of intermediate(G299) as a white powder and 0.237 g of intermediate (G300) as a whitepowder.

Reaction scheme:

Intermediate (G311): A solution of intermediate (D30) (500 mg; 0.721mmol), 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (249mg; 0.865 mmol) and K₃PO₄ (459 mg; 2.16 mmol) in 1,4-dioxane (10 mL) andwater (3 mL) was purged by N₂ bubbling for 10 min before the addition ofPdCl₂dtbpf (47 mg; 72.1 μmol). The resulting mixture was purged by N₂bubbling, then heated at 80° C. using a single mode microwave (Biotage®Initiator EXP 60) with a power output ranging from 0 to 400 W for 30minutes. The mixture was poured into DCM, washed with water (twice),brine, dried over MgSO₄, filtered and evaporated in vacuum. The compoundwas purified by preparative LC (Irregular SiOH 15-40 μm, 25 g Grace®,liquid loading (DCM), mobile phase gradient: from Heptane/EtOAc 100:0 to60:40. The fractions containing product were combined and the solventwas removed in vacuum to give 385 mg (44%) of intermediate (G311).

Intermediate (G312): Pd/C 10% (80 mg; 75.2 μmol) was added to a degassedsolution of intermediate (G311) (383 mg; 0.738 mmol) in MeOH (6 mL) andAcOEt (6 mL). The resulting mixture was hydrogenated at rt under 1 barovernight. EtOAC was added and the mixture was filtered through a pad ofCelite®, the filtrate was concentrated until dryness to give 385 mg(quant.) of intermediate (G312) as a off-white foam.

Intermediate (G313): A mixture of intermediate (G312) (363 mg; 0.697mmol) in HCl 3M (2 mL) and THF (2 mL) was stirred at 50° C. for 2 days.HCl 3M (2 mL) and THF (2 mL) were added and the mixture was stirred at50° C. for 4 days. Water was added and the mixture was extrated withEt₂O (twice). The combined organic layers were washed with an aqueoussolution of NaHCO₃ (once) and water (twice), then dried over MgSO₄,filtered, concentrated and purified by preparative LC (Irregular SiOH 30μm, 40 g Grace®, liquid loading (DCM), mobile phase gradient: fromHeptane/EtOAc 100:0 to 50:50). The fractions containing product werecombined and the solvent was removed in vacuum to give 220 mg (66%) ofintermediate (G313) as a white solid.

Intermediate (G314): LiHMDS 1.5 M in THF (0.8 mL; 1.2 mmol) was added toa stirred solution of intermediate (G313) (220 mg; 0.462 mmol) andPhNTf₂ (430 mg; 1.2 mmol) in THF (10 mL) at −78° C. and under N₂. Theresulting mixture was stirred at −78° C. for 4 h. The mixture wasquenched by addition of water and extrated with EtOAc (twice). Thecombined organic layers were dried over MgSO₄, filtered and evaporatedin vacuum to give 470 mg (quant.; purity 60%) of intermediate (G314) asa yellow solid. The product was used as such in the next step.

Intermediate (G315): A suspension of intermediate (G314) (470 mg; 0.463mmol; purity 60%) and K₂CO₃ (77 mg; 0.556 mmol) in MeOH (4 mL) wasdegassed by N₂ bubbling for 15 min before the addition of Pd(OAc)2 (10mg; 44.5 μmol) and dppp (20 mg; 48.5 μmol). The resulting mixture waspurged with CO (3×) then pressurised with CO (10 bar) and heated at 120°C. overnight.The mixture was filtered through a pad of Celite® and thecelite was washed with EtOAc. Water was added and the organic layer wasseparated, washed with brine, dried over MgSO₄, filtered, concentratedand purified by preparative LC (Irregular SiOH 30 μm, 40 g Grace®,liquid loading (DCM), mobile phase gradient: heptane/AcOEt from 90:10 to40:60) to give 134 mg (56%) of intermediate (G315) as white foam.

Intermediate (H)

Intermediate (I11): A mixture of5-(4-bromo-2-fluorophenyl)-1H-pyrazol-3-amine, (10 g, 39 mmol) anddimethylacetylendicarboxylate (5.54 g, 39 mmol) in AcOH (250 mL) wasstirred at RT for 6 hours. The solvent was evaporated and water wasadded to the residue. The precipitate was filtered off and dried to give7.75 g (54%) of intermediate (H1).

The following intermediates were prepared according to the aboveprocedure:

Intermediate (I)

Intermediate (I1): A suspension of intermediate (H1) (7.75 g, 21.1 mmol)in POCl₃ (100 mL) was heated at reflux for 12 hours. POCl₃ wasevaporated and the residue was taken up in aqueous solution of Na₂CO₃.The solid was filtered off to give 8.23 g (quant.) of intermediate (I1).

The following intermediates were was prepared according to the aboveprocedure:

Intermediate (I3): N,N-dimethylaniline (4.2 g, 34.7 mmol) was added to asuspension of intermediate (H2) (3.5 g, 11 mmol) in POCl₃ (90 mL) andthe reaction mixture was heated at reflux for 12 hours. POCl₃ wasevaporated and the residue was taken up in aqueous solution of Na₂CO₃.The solid was filtered off to give 1.52 g (41%) of intermediate (I3).

Intermediate (I4): Intermediate (H3) (1 g, 2.87 mmol) was heated atreflux in POCl₃ (10 mL) until it dissolved. After cooling down to RT,the reaction mixture was diluted with ether, then the precipitate wasfiltered off and washed with ether to give 0.45 g (40%) of intermediate(I4).

The following intermediate was prepared according to the aboveprocedure:

Intermediates (J), (K), (L), (M), (N), (O), (P), First Approach

Second Approach

Intermediate (J)

Intermediate (J1): Hydrazine hydrate (5 mL, 0.12 mol) was added to asolution of 2-fluoro-4-nitro-benzoic acid methyl ester (10.5 g, 0.05mol) in anhydrous EtOH (100 mL). The reaction mixture was heated atreflux for 4 hours. Then, the solvent was evaporated under reducedpressure and the crude intermediate (J1) was used without purificationfor the next step.

Intermediate (K)

Intermediate (KI): S-methylisothiouronium sulfate (7.0 g, 0.05 mol) wasadded to a solution of intermediate (J1) (0.05 mol) in NaOH (1% aqueoussolution) (250 mL). The resulting mixture was stirred for 12 hours. Theprecipitate was filtered off, washed with ice-water and dried. Theresidue was dissolved in water and the reaction mixture was heated atreflux for 26 hours. The precipitate was filtered off, washed withice-water and dried to give 2.5 g (21% by 2 steps) of intermediate (K1).

Intermediate (L)

Intermediate (LI): Ethyl 2,4-dioxohexanoate (1.9 g, 11.0 mmol) was addedto a stirred solution of intermediate (K1) (2.5 g, 11.0 mmol) inanhydrous EtOH (50 mL). The reaction mixture was heated at reflux for 1hour. The solvent was evaporated. The residue was purified by columnchromatography (silica gel, DCM/EtOAc). The pure fractions werecollected and the solvent was evaporated. The residue was purified byre-crystallization from EtOH to give 0.7 g (18%) of intermediate (L1).

Intermediate (L2): A mixture of 3-(2-thienyl)-/H-1,2,4-Triazol-5-amine(1.00 g, 6 mmol) and ethyl 2,4-dioxohexanoate (1.03 g, 6 mmol) in dryEtOH (50 mL) was heated at reflux for 2 hours. After cooling down to RT,the precipitate was filtered off and dried to give 0.7 g (39%) ofintermediate (L2).

Intermediate (M)

Intermediate (M1): KOH (0.22 g, 3.9 mmol) was added to a stirredsolution of intermediate (L1) (0.7 g, 1.9 mmol) in EtOH (10 mL). Thereaction mixture was stirred at RT for 1 hour. The solvent wasevaporated and the residue was taken up with water and washed withether. The aqueous layer was neutralized with HCl cc (0.35 mL) to pH 7.The precipitate was filtered off and dried to give 0.6 g (99%) of theintermediate (M1).

Intermediate (M2): KOH (0.259 g, 4.6 mmol) was added to a solution ofintermediate (L2) (0.70 g, 2.3 mmol) in EtOH (25 mL). The reactionmixture was stirred at RT for 1 hour. The solvent was evaporated, thenthe residue was taken up with water and washed with ether. The aqueouslayer was neutralized with HCl cc to pH 7. The precipitate was filteredoff and dried to give 0.56 g (88%) of intermediate (M2).

Reaction scheme:

Intermediate (N)

Intermediate (N1): TBTU (0.68 g, 2.1 mmol) was added to a mixture ofintermediate (M1) (0.6 g, 1.8 mmol), 2-methylazepane (0.24 g, 2.1 mmol)and DIEA (0.5 mL, 2.9 mmol) in DCM (50 mL). The reaction mixture wasstirred at RT overnight. The reaction mixture was poured into water. Theorganic layer was separated, washed with brine, dried over sodiumsulfate, filtered and evaporated. The residue was purified by columnchromatography (silica gel, DCM). The pure fractions were collected andthe solvent was evaporated to give 0.7 g (90%) of intermediate (N1).

Intermediate (N2): Intermediate (N1) (0.7 g, 1.6 mmol) was dissolved inMeOH (10 mL) and Pd/C (0.1 g) was added. The reaction mixture was shakenfor 2 h at RT under hydrogen (1 bar). Then, the solution was filteredthrough a pad of Celite® to remove the catalyst and the filtrate wasevaporated. The residue was purified by re-crystallization fromEtOAc/ether to give 0.63 g (99%) of intermediate (N2).

Intermediate (N3): (diacetoxyiodo)benzene (7.27 g, 22.6 mmol) was addedto a solution of intermediate (Q1) (8.70 g, 22.6 mmol) in dry DCM (100mL) at 0° C. The reaction mixture was stirred at RT for 12 hours. Thesolvent was evaporated and the residue was purified by columnchromatography (silica gel, EtOAc). The pure fractions were collectedand the solvent was evaporated. The residue was heated at 200° C. for 48hours. The crude product was purified by HPLC. The pure fractions werecollected and the solvent was evaporated to give 1.2 g of intermediate(N3).

Intermediate (N4): Pd(PPh₃)₄ (150 mg, 0.13 mmol) was added to a solutionof intermediate (N3) (300 mg, 0.65 mmol), KCN (170 mg, 2.6 mmol) and CuI(10 mg) in anhydrous CH₃CN (5 mL). The reaction mixture was heated at160° C. for 2 hours using one single mode microwave with a power outputranging from 0 to 400 W. The solvent was evaporated. The residue waspurified by column chromatography (silica gel, DCM/EtOAc). The purefractions were collected and the solvent was evaporated to give 170 mg(64%) of intermediate (N4).

Intermediate (0)

Intermediate (01): The mixture of6-ethyl-2-(methylthio)-4-pyrimidinecarboxylic acid (4.73 g, 23.9 mmol),BOP (11.79 g, 26 mmol) and DIEA (4.61 g, 36 mmol) and 2-methyl-azepane(2.97 g, 26 mmol) in dry DMF (25 mL) was stirred at RT for 6 hours. Thesolvent was evaporated, then the mixture was washed with water andextracted with CHCl₃. The residue was purified by column chromatography(silica gel, hexane/EtOAc (2/1)). The pure fractions were collected andthe solvent was evaporated to give 5.55 g (79%) of intermediate (O1).

Intermediate (P)

Intermediate (P1): The mixture of intermediate (01) (5.55 g, 18.9 mmol)and hydrazine hydrate (50 mL) in EtOH (50 mL) was heated at reflux for48 hours. The solvent was evaporated and the residue was purified bycolumn chromatography (silica gel, THF). The pure fractions werecollected and the solvent was evaporated to give 5.25 g (100%) ofintermediate (P1).

Intermediate (0)

Intermediate (Q1): The mixture of intermediate (P1) (5.25 g, 19 mmol)and 2-fluoro-4-bromobenzaldehyde (3.84 g, 19 mmol) was heated at refluxfor 12 hours. The solvent was evaporated to give 8.70 g (100%) ofintermediate (Q1). The product was used without purification for thenext step.

Intermediate (R):

Intermediate (R1): Trimethylsulfoxonium iodide CAS [1774-47-6 ] (10.6 g;48.3 mmol) was added to a mixture of NaH (60% dispersion in mineral oil)(1.9 g; 48 mmol) in DMSO (330 mL) at RT. The resulting mixture wasstirred at RT for 20 min then (2E)-3-(4-bromo-3-fluorophenyl)-ethylester CAS [1173119-94-2] (11 g; 40 mmol) was added. The resultingmixture was stirred at RT for 24 hours then 60° C. for 24 hours. Waterand EtOAc were added and the layers were separated. The aqueous layerwas extracted with EtOAc (once). The combined organic layers were washedwith brine, dried over MgSO₄, filtered and the solvent was removed invacuum. The residue was triturated in EtOAc, filtered (the solid wasdiscarded). The mother liquor was evaporated and purified by columnchromatography (silica gel, from heptane/EtOAc 100/0 to 90/10). The purefractions were collected and evaporated to give 3.45 g (30%) ofintermediate (R1) as a mixture of trans isomers.

The following intermediate was prepared according to the aboveprocedure:

Reaction scheme:

Intermediate (R2): A mixture of 4-bromo-3-fluorobenzaldehyde CAS[105942-08-3] (11.4 g; 56.2 mmol) and(tert-butoxycarbonylmethylene)triphenylphosphorane (25.4 g; 67.5 mmol)in dry toluene (100 mL) was stirred at 80° C. for 2 hours. Water wasadded and the layers were separated. The aqueous layer was extractedwith EtOAc (twice). The combined organic layers were dried over MgSO₄,filtered and the solvent was removed in vacuum to give a white solidwhich was triturated in heptane and filtered (twice). The precipitate(PPh₃O) was discarded and the filtrate was evaporated to dryness to givecrude compound. The solid was recrystallized in heptane, filtered andwashed with heptane to give 5.4 g (32%) of intermediate (R2) as a whitesolid.

The following intermediates were prepared according to the aboveprocedure:

Intermediate (E-R4)-(Z-R4): (Carbethoxymethylene)-triphenylphosphorane(144 g; 414 mmol) was added portionwise to a mixture of3-bromo-2-fluoro-benzaldehyde (70 g; 345 mmol) in toluene (700 mL) withtemperature control (ice bath). Then the reaction mixture was stirred at80° C. for 18 h. Water was added and the layers were separated. Theaqueous layer was extracted with EtOAc (twice). The combined organiclayers were dried over MgSO₄, filtered and the solvent was removed invacuum to give a white solid. The solid was triturated in Et₂O andfiltered. The solid was discarded (PPh₃O) and the filtrate wasevaporated to dryness. The residue was purified by preparative LC(irregular SiOH, 15-40 μm, 1080 g (330 g +750g), Grace Resoiv®, liquidloading (Heptane), mobile phase gradient: from heptane/DCM 80/20 to50/50) to give 93.5 g of a solid. The solid was purified again bypreparative LC (irregular SiOH, 15-40 μm, 1500 g, Grace Resoiv®, liquidloading (Heptane), mobile phase gradient: from heptane/DCM 80/20 to50/50) 42.5 g of a mixture of intermediate (E)-R4 and (Z)-R4 and 53.2 g(55%) of pure intermediate (E)-R4. 28.8 g of mixture of intermediates(E)-R4 and (Z)-R4 were purified via achiral SFC (Stationary phase:Chiralcel® OD-H 5n.m 250*30 mm, Mobile phase: 90% CO₂, 10% iPrOH) togive 4.37 g (5%) of pure intermediate (Z)-R4 and 22.0 g (23%) ofintermediate (E)-R4 as a colorless oil.

Intermediate (R9): A mixture of intermediate R1 (6.60 g; 21.8 mmol) andLiOH.H₂O (2.75 g; 65.5 mmol) in THF (100 mL) and H₂O (50 mL) was stirredat rt for 18 h. An aqueous solution of KHSO₄ (10%) and EtOAc were addedto the reaction mixture and the organic layer was separated. The aqueouslayer was extracted with EtOAc (twice). The combined organic layers weredried over MgSO₄, filtered and evaporated in vacuum. The residue waspurified by preparative LC (irregular SiOH 15-40 μm, 120 g GraceResolv®,dry loading (SiOH), mobile phase gradient: from heptane/EtOAc/AcOH90/10/0.25 to 60/40/1) to give 4.00 g (71%) of intermediate (R9) as awhite solid.

Intermediate (R10): A mixture of intermediate (R9) (4.0 g; 15.4 mmol),L-menthol (2.90 g; 18.5 mmol), COMU® (9.92 g; 23.2 mmol) and DIEA(corrected) (8.0 mL; 46 mmol) in DMF (150 mL) was stirred at rtovernight. H₂O and 50 mL of HCl 1M were added and the mixture wasextrated with EtOAc (3 times). The combined organic layers were driedover MgSO₄, filtered and evaporated in vacuum. The residue was dissolvedin DMF (100 mL) and L-menthol (2.90 g; 18.5 mmol), COMU® (9.92 g; 23.2mmol) and DIEA (8.0 mL; 46 mmol) were added and stirred at rt overnight.Brine was added and the mixture was extracted with EtOAc (3 times). Thecombined organic layers were dried over MgSO₄, filtered and evaporatedin vacuum. The residue was purified by preparative LC (irregular SiOH15-40 μm, 220 g Graceresolv®, liquid loading (DCM), mobile phasegradient: from Heptane/EtOAc/AcOH 98/2/0.625 to 60/40/1). The fractionscontaining product were combined and the solvent was removed in vacuo togive 4.2 g of a mixture of 2 diastereomers as colorless oil. The mixturewas purified via chiral SFC (Stationary phase: CHIRALPAK® IC 5 μm 250×30mm, Mobile phase: 93% CO₂, 7% iPrOH) to give 2.23 g of firstdiastereomer intermediate (R10′) (*S,*S) as a white solid and 1.98 g ofa second diastereoisomer intermediate (R10) (*R,*R) as white solid.

Reaction scheme:

Intermediate (R7): 19.9 g of intermediate (R9) were purified via chiralSFC (Stationary phase: Lux cellulose® 2 5 μm 250*21.2 mm, Mobile phase:80% CO₂, 20% iPrOH(1.0% iPrNH₂)) to give 10.9 g of the firstdiastereomer (*S,*S) and 12.7 g of the second diastereomer (*R,*R)intermediate (R7).

Intermediate (R8): H₂SO₄ 98% (9.80 mL; 184 mmol) was added to a solutionof intermediate (R7) (12.7 g; 36.8 mmol) in EtOH (170 mL) at rt. Thereaction mixture was stirred at rt for 18 h. Then an aqueous solution ofNaHCO₃, brine and EtOAc were added to the reaction mixture. The layerswere separated. The aqueous layer was extracted with EtOAc (twice). Theorganic layer was dried over MgSO₄, filtered and dried to give 11.5 g(quant) of intermediate (R8).

Reaction scheme:

Intermediate (R11): At 0° C., under N₂, NaH 60% (310 mg; 7.75 mmol) wasadded to a solution of tris-(1-methylethyl)-sulfoxonium (2.5 g; 7.57mmol) in DMF (60 mL). The mixture was stirred for 15 min before the slowaddition of intermediate R2 (1.7 g; 6.23 mmol) in DMF (40 mL). Thereaction mixture was stirred at rt for 42 h. Water was added dropwise.Then HCl 1M, brine and EtOAc were added. The layers were separated. Theaqueous layer was extracted with EtOAc (twice). The combined organiclayers were washed with brine, dried over MgSO₄, filtered, evaporatedand purified by preparative LC (irregular SiOH 15-40 μm, 120 g Grace®,loading (DCM), mobile phase gradient: from Heptane/EtOAc 100/0 to 90/10in 10 CV) to give 60 mg of intermediate (R11).

Reaction scheme:

Intermediate (R13): Under N₂ at 0° C., 4-chloro-3-fluorophenylmagnesiumbromide 0.5M in THF (2 mL; 1 mmol) was added slowly (over about 7 min)to a solution of methyl 6-oxo-spiro[3.3]heptane-2-carboxylate (168 mg; 1mmol) in dry Et₂O (10 mL). The mixture was stirred at 0° C. for 3 h. 10%aq. NH₄Cl was added and an extraction was performed with EtOAc. Theorganic layer was washed with brine, dried (MgSO₄), evaporated andpurified by preparative LC (irregular SiOH 15-40 μm, 40 g Grace® Resolv,liquid loading (DCM), mobile phase gradient: from heptane/EtOAc from100:0 to 0:100) to give 152 mg (50%) of intermediate (R13) as acolorless gum.

Intermediate (R14): TFA (5 mL; 65.3 mmol) was added slowly at 0° C. to amixture of Intermediate (R13) (2 g; 6.70 mmol) and TES (1.2 mL; 7.51mmol) in DCM (40 mL). The mixture was stirred at 0° C. for 1 h and at rtfor 3 h. NaOH 1N was added (until basic pH). The mixture was extractedwith DCM. The organic layer was separated, washed with brine, dried(MgSO₄), evaporated and purified by preparative LC (irregular SiOH 15-40p.m, 120 g Grace® Resolv, liquid loading (DCM), mobile phase gradient:from heptane/EtOAc from 100:0 to 80:20) to give 1.01 g (53%) ofintermediate (R14) as a colorless oil.

Reaction scheme:

Intermediates (R15a/R15b): LiHMDS 1.5 M in THF (0.41 mL, 617 μmol) wasadded to a solution of ethyl-3-oxocyclohexanecarboxylate (100 mg, 588μmol) in THF (1.3 mL) at −78° C. The resulting mixture was stirred at−78° C. for 1 h before the addition of PhNTf₂ (220 mg, 617 μmol) in THF(1.3 mL). The mixture was stirred at −78° C. for 30 min and then allowedto warm to rt overnight. The mixture was quenched by addition of NH₄Clsat. (0.86 mL) and the solvent was removed under vacuum. Et₂O and anaqueous solution of NaOH (0.3 M) were added and the layers wereseparated. The organic layer was washed with an aqueous solution of NaOH(0.3 M) (once), a saturated aqueous solution of NH4Cl (once) and brine(once), dried over MgSO₄, filtered and concentrated in vacuum to give143 mg of a mixture of intermediate (R15a) and intermediate (R15b) asyellow oil. The crude product was used without further purification inthe next step.

Reaction scheme:

Intermediate (R17):AcCl (0.28 mL; 4.0 mmol) was added dropwise to amixture of 3-(4-bromo-3-fluorophenyl)-2-Propen-1-ol (0.84 g; 3.64 mmol)and TEA (1.0 mL; 7.3 mmol) in DCM (36 mL) and the mixture was stirred atrt for 4 h. An extra amount of AcCl (524 μL; 0.73 mmol) and DMAP (22 mg;0.182 mmol) were added and the mixture was stirred at rt for 16 h. Anextra amount of AcCl (0.13 mL; 1.8 mmol) was added and the mixture wasstirred at rt for 48 h. The reaction was diluted with DCM and an aqueoussolution of NaHCO₃ (10%). The aqueous layer was extracted with DCM(once). The combined organic layers were dried over MgSO₄, filtered andthe solvent was removed in vacuo to give 983 mg of intermediate (R17).

Intermediate (R18): Trimethylsilyl-(fluorosulfonyl)-difluoroacetate (2.2mL; 11 mmol) in toluene (9 mL) was added dropwise over 6 h (with asyringe pump) to a mixture of intermediate (R17) (1.2 g; 4.4 mmol) andNaF (18 mg; 0.43 mmol) in toluene (8 mL) at 105° C. The resultingmixture was stirred at 105° C. for 16 h. An extra amount ofTrimethylsilyl-(fluorosulfonyl)-difluoroacetate (2.2 mL; 11 mmol) intoluene (2 mL) was added dropwise over 4 h (with a syringue pump). Themixture was evaporated and purified by preparative LC (regular SiOH, 30μm, 80 g interchim®, liquid loading (DCM), mobile phase gradient: fromheptane/toluene 50/50 to 0/100) to give 0.63 g (44%) of intermediate(R18).

Intermediate (R19): B₂pin₂ (0.560 g, 2.20 mmol) and KOAc (0.360 g, 3.66mmol) were added to a solution of intermediate (R4) (0.500 g, 1.83 mmol)in dioxane (6 mL) at rt. The mixture was purged (twice) with argon andPdCl₂dppf (0.134 g, 0.183 mmol) was added. The mixture was purged again(twice) with argon and stirred at 100° C. for 16 h. The reaction mixturewas quenched with H₂O and extracted with DCM (50 mL). The organic layerwas dried (Na₂SO₄), filtered and concentrated under reduced pressure.The residue was purified by flash column chromatography (Regular SiOH;50 μm, Interchim® 40 g, mobile phase gradient: from cyclohexane/EtOAc98/02 to 50/50). The desired fraction was collected and evaporated invacuo to give 0.850 g (100%) of intermediate (R19) as brown oil.

The following intermediate was prepared according to intermediate (R19):

Intermediate (S):

Intermediate (Si): In a stainless-steel bomb, to a degassed mixture of2-amino-6-bromo-1-fluoronaphtalene CAS [247924-62-5] (988 mg; 4.12 mmol)and Et₃N (1.4 mL; 10.1 mmol) in MeOH (28 mL) was added PdCl₂(dppf) (212mg; 0.289 mmol). The resulting mixture was carbonylated under 15 bar ofCO for 24 hours at 130° C. The mixture was cooled to RT and evaporatedto dryness to give 1.91 g of crude product which was purified by columnchromatography (silica gel, from heptane/EtOAc 80/20 to 50/50).The purefractions were collected and evaporated to give 801 mg (89%) ofintermediate (Si).

Intermediate (S2): To a mixture of CuBr (1.15 g; 5.15 mmol) and t-butylnitrite CAS [540-80-7] (613 μL; 5.15 mmol) in CH₃CN (45 mL) was addedintermediate (51) (753 mg; 3.44 mmol). The resulting mixture was stirredat 65° C. for 2 hours. Water was added and the mixture was extractedwith EtOAc (twice). The combined organic layers were washed with brine,dried over MgSO₄, filtered and the solvent was removed in vacuum to give870 mg of crude product which was purified by column chromatography(silica gel, from heptane/EtOAc 100/0 to 70/30). The pure fractions werecollected and evaporated to give 350 mg (36%) of intermediate (S2).

Intermediate (S3): A mixture of intermediate (S2) (350 mg; 1.24 mmol)and LiOHH₂O (78 mg; 1.85 mmol) in THF (7 mL) and H₂O (3.5 mL) wasstirred at RT for 64 hours. Water was added and the mixture was washed(twice) with DCM. The aqueous layer was acidified with 3N HCl andextracted with DCM (3 times). The combined organic layers were driedover MgSO₄, filtered and evaporated to dryness to give 337 mg (100%) ofintermediate (S3).

Reaction scheme:

Intermediate (S4): A mixture of 4-bromo-3-fluoro-2-hydroxybenzaldehyde(2.8 g; 12.8 mmol), methyl acrylate ester (6.9 mL; 76.7 mmol) and1,4-diazabicyclo[2.2.2]octane (287 mg; 2.56 mmol) was heated at 150° C.using a singlemode microwave (Biotage® initiator60) with a power outputranging from 0 to 400 W for 45 minutes. The reaction mixture wasconcentrated to dryness. Water and brine were added and the aqueouslayer was extracted with DCM (twice). The organic layer was dried overMgSO₄, filtered and concentrated to give crude product which waspurified by column chromatography (silica gel, from heptane/EtOAc: 95/5to 50/50) to give 1.23 g (30%) of intermediate (S4) as a white solid.

Reaction scheme:

Intermediate (SS): 1,1′-Difl t kxo-2,2′-bipy ri dinium bi s (tetrail uorob orate) (MEC-31) CAS[178439-26-4] (6.5 g; 18 mmol) was added to asolution of 6-methoxy carbonyl-2-naphthol [17295-11-3] (3.0 g; 15 mmol)in CH₃CN (75 mL). The reaction mixture was stirred at 70° C. for 5 h. Anaqueous solution of HCl (1N) and DCM were added and the precipitate wasfiltered off. The filtrate was decanted and the aqueous layer wasextracted with DCM (once). The combined organic layers were washed withbrine, dried over MgSO₄, filtered and the solvent was removed in vacuoto give 3.7 g of difluoro intermediate as an orange solid. Difluorointermediate was hydrogenated in EtOH (147 mL) with Pd/C (10%) (971 mg)as catalyst at rt under 1 bar of hydrogen for 16 h. The mixture wasfiltered over celite and the cake was rinced with EtOH. The filtrate wasevaporated to dryness and was purified by preparative LC (regular SiOH,30 um, 80 g interchim®, dry loading, mobile phase gradient: fromheptane/EtOAc 100/0 to 60/40) to give 328 mg of intermediate (S5) and2.2 g of a mixture of CAS [17295-11-3] and intermediate (S5) (25:75).

Intermediate (S6): N-phenyltrifluoromethanesulfonimide (672 mg; 1.88mmol) and Et₃N (328 μL; 2.37 mmol) were added to a solution ofintermediate (S5) (345 mg; 1.57 mmol) in DCM (4.5 mL) at rt and thereaction mixture was stirred at rt for 16 h. Then an aqueous solution ofHCl (1M) was added. The aqueous layer was extracted with DCM (once). Theorganic layer was washed with an aqueous saturated solution of NaHCO3,then with brine, dried over MgSO₄, concentrated and purified bypreparative LC (irregular SiOH, 15-40 um, 12 g Grace resolve®, dryloading (on Celite®), mobile phase gradient: from Heptane/EtOAc 90/10 to40/60) to give 590 mg (87%) of intermediate (S6) as a colorless oilwhich crystallized on standing.

Reaction scheme:

Intermediate (S7)

In a Schlenck tube, MEC-31 CAS [178439-26-4] (2 g; 5.52 mmol) was addedto a solution of 7-hydroxy-2-naphthalenecarboxylic acid methyl ester (1g; 4.60 mmol) in CH₃CN (23 mL). The reaction mixture was stirred at 70°C. for 16 hours. The reaction mixture was concentrated, water and anaqueous saturated solution of NaHCO₃ were added, and the aqueous layerwas extracted with DCM (3 times). The organic layer was dried over MgSO₄and concentrated. The residue was purified by preparative LC (irregularSiOH, 15-40 μm, 10 g Merck®, dry loading (on SiOH), mobile phasegradient: from Heptane/EtOAc 90/10 to 40/60) to give 175 mg of pureintermediate (S7) (17%) as a white solid and 748 mg of impureintermediate (S7) as a yellow oil (purity 55%).

Intermediate (S8): The formation of intermediate (S8) followed the sameprocedure than intermediate (S6).

Intermediate (S9): Ethyl diazoacetate (1.15 mL, 11.0 mmol) was addeddropwise to a solution of 4-bromo-3-fluorosalicylaldehyde (0.400 g, 1.83mmol) and tetrafluoroboric acid diethyl ether complex (0.050 mL, 0.37mmol) in DCM (4 ml) at rt. After 2 h, the solvent was evaporated andconcentrated H₂SO₄ (0.6 ml) was added. After 10 min, the reactionmixture was diluted with 10 mL of DCM and neutralized with saturatedaqueous NaHCO₃ (10 ml). The solution was extracted with DCM (2×20 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a yellow oil.The crude waspurified by preparative LC (irregular SiOH, 40-63 μm, Fluka® mobilephase gradient: from pentane/EtOAc 100/00 to 90/10) to give 0.190 g(38%) of intermediate (S9) as white solid.

Intermediate (S)

Intermediate (S10): To a solution of intermediate (S4) (0.237 g; 0.83mmol) in EtOAc (9.5 mL) and MeOH (1.6 mL) degassed with N₂, were addedAl₂O₃ (0.0051 g; 0.05 mmol) and Rhodium on activate charcoal (0.085 g,0.041 mmol) and the mixture was hydrogenated under an atmosphericpressure of H₂ at room temperature for 16 h. The solution was filteredoff on a pad of Celite® and the solvent was removed under reducedpressure to give 0.219 g (92%) of intermediate (S10) as colorless oilwhich crystallized on standing.

Intermediate (S11): Ethyl bromoacetate (0.33 ml, 2.97 mmol) was added toa solution of 3-bromo-2-fluoro-6-hydroxy-benzaldehyde (0.5 g, 2.28 mmol)and K₂CO₃ (0.63 g, 4.57 mmol) in DMF (5 ml) at room temperature. Thereaction mixture was heated at 120° C. for 1.5 h, cooled to roomtemperature and filtered through a short pad of Celite®. The filtratewas acidified to pH 2 with HCl 3N and the solution was extracted withDCM (2×25 ml). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude was purifiedby column chromatography (silica gel, mobile phase pentane/EtOAc 100/00to 90/10) to give after evaporation 0.252 g (38%) of intermediate (S11)as white solid.

Intermediate (S12): Methyl acrylate (1.96 ml, 21.9 mmol) and DABCO(0.082 g, 0.730 mmol) were added to3-bromo-2-fluoro-6-hydroxy-benzaldehyde (0.850 g, 3.65 mmol) at rt. Thereaction mixture was stirred at 150° C. for 45 minutes using asinglemode microwave (Biotage® initiator60) with a power output rangingfrom 0 to 400 W. The reaction mixture was concentrated to dryness. Theresidue was purified by column chromatography (silica gel, mobile phasecyclohexane/EtOAc 98/02 to 50/50). The desired fraction was collectedand evaporated in vacuo to give 0.230 g (22%) of intermediate (S12) as awhite powder.

Intermediates (T)

Intermediate (Ti): To a solution of1-(2,2,5-trimethyl-1,3-dioxan-5-yl)-ethanone (8.4 g, 48.8 mmol) in THF(84 ml) was added NaH 60% in mineral oil (2.9 g, 73.2 mmol) and theresulting mixture was stirred at rt for 30 min. To the resultingreaction mixture was added dimethyl oxalate (8.6 g, 73.2 mmol) and themixture was heated at reflux for 2 h. After cooling to rt the mixturewas quenched with saturated aqueous NH₄Cl (50 ml), extracted with EtOAc(3 times), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude was purified by column chromatography (silica gel,mobile phase: pentane/EtOAc 90/10) to give 4 g (32%) of intermediate(T1) as an orange oil. The following intermediate was prepared accordingto intermediate (T1):

Intermediates (U)

Intermediate (U!): A solution of 1-Bromo-2-fluoro-4-iodobenzene (0.5 g,1.66 mmol), Sarcosine (0.37 g, 4.15 mmol), K₂CO₃ (0.23 g, 1.66 mmol) andCuI (0.063 g, 0.33 mmol) in DMF (13 mL) was purged with N₂ flow for 5min and then stirred and heated at 90° C. overnight. The solution wascooled down to room temperature. Water was added and the aqueous layerwas acidified with HCl 3N. The organic layer was extracted with EtOAc,washed with water, dried over MgSO₄, filtered and evaporated to give0.41 g (94%) of intermediate (R5) as an orange oil.

Reaction scheme:

Intermediate (U2): Formaldehyde (1.51 mL, 20.11 mmol) was added to asolution of Methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate (0.78 g,5.03 mmol) in MeOH (8 mL) and THF (8 mL) at room temperature and thesolution was stirred 1 hour at room temperature. Then sodium borohydride(0.95 g, 25.14 mmol) was added and the mixture was stirred at 60° C.overnight. The mixture was poured out into ice, the organic layer wasextracted with CH₂Cl₂, dried over MgSO₄, filtered off and evaporatedtill dryness to give 0.218 g (22%) of intermediate (U2).

Reaction scheme:

Intermediate (U3): A solution of methylcis-3-(Boc-amino)-cyclobutanecarboxylate (0.95 g, 4.14 mmol), MeI (0.28mL, 4.56 mmol) and KOH (0.26 g, 4.56 mmol) in DMF (32 mL) was stirred atroom temperature overnight. Then the solution was diluted with EtOAc.The organic layer was washed with water (4×) then brine, dried overMgSO₄ and concentrated under reduced pressure. DMF (32 mL) was added tothe residue and then iodomethane (0.28 mL, 4.56 mmol) and KOH (0.26 g,4.56 mmol) were added, the resulting solution was stirred at roomtemperature overnight. Then the solution was diluted with EtOAc. Theorganic layer was washed with water (4×) then brine, dried over MgSO₄and concentrated under reduced pressure to give 0.636 g (54%) ofintermediate (U3) as colorless oil.

Intermediate (U4): HCl 4M in dioxane (10.29 mL, 41.15 mmol) was added toa solution of intermediate (U3) (0.589 g, 2.06 mmol) in 1, 4-dioxane(35.2 mL) at room temperature and the solution was stirred overnight at50° C. The solution was concentrated under reduce pressure affording0.436 g (94%) of intermediate (U4) as a colorless oil.

Reaction scheme:

Intermediate (U5): In a sealed tube, (4-bromo-3-fluorophenyl)-hydrazine(931 mg; 4.54 mmol) was added at 0° C. to a solution of ethyl2-formyl-3-oxopropanoate (654 mg; 4.54 mmol) in EtOH (3.8 mL). Thereaction mixture was stirred at rt for 18 hours. The solid was filteredoff, washed with EtOH and dried on frit to give 1.21 g (85%) ofintermediate (U5) as a pale orange solid.

Reaction scheme:

Intermediate (U6): In a Schlenk tube, a solution of4-Chloro-3-fluoroiodobenzene (7.3 g, 28.4 mmol), K₃PO₄ (16.1 g, 75.9mmol), (S)-methylpyrrolidine-3-carboxylate hydrochloride (3.1 g, 19.0mmol) and P(tBu)₃.HBF₄ (551 mg, 1.90 mmol) in dioxane (150 mL) waspurged with N₂ (3×). Pd(OAc)₂ (213 mg; 0.95 mmol) was added and thereaction mixture was stirred at 100° C. for 16 h, then cooled down tort. The mixture was diluted with EtOAc and water. The layers wereseparated. The aqueous layer was extrated with EtOAc (twice). Thecombined organic layers were washed with brine, dried over MgSO₄,filtered and the solvent was removed under reduced pressure. The residuewas purified by preparative LC (irregular SiOH, 15-40 μm, 220 g Grace®,liquid injection (Heptane), mobile phase gradient: from Heptane 100%, toheptane 70%, EtOAc 30%) to give 1.91 g (37%) of intermediate (U6) as anorange oil.

Intermediate (U7): A mixture of intermediate (U6) (3.88 g; 8.28 mmol;55%), B₂pin₂ (3.15 g; 12.4 mmol) and KOAc (1.6 g; 16.6 mmol) in dioxane(70 mL) was purged with nitrogen. Pd₂dba₃ (758 mg; 0.828 mmol) and XPhos(395 mg; 0.828 mmol) were added and the mixture was purged with nitrogenthen stirred for 18 hours at 110° C. EtOAc and water were added. Themixture was filtered over a pad of Celite® and the filtrate wasdecanted. The organic layer was washed with brine (once), dried overMgSO₄, concentrated and purified by preparative LC (Irregular SiOH,15-40 μm, 220 g Grace®, dry loading (on SiOH), mobile phase gradient:from heptane/EtOAc 90/10 to 50/50) to give 1.85 g (64%) of intermediate(U7) as a beige solid.

The following intermediate was prepared according to intermediate (U7):

C. Synthesis of the Final Compounds

Compound (A)

Compound (A1): A mixture of intermediate (E8) (100 mg, 0.37 mmol), BOP(181 mg, 0.40 mmol), DIEA (71 mg, 0.55 mmol) and 2-methylazepanehydrochloride (0.40 mmol) in dry DMF (25 mL) was stirred at RT for 6hours. The solvent was evaporated, then the residue was taken up inCHCl₃ and washed with water. The organic layer was separated, dried oversodium sulfate and evaporated till dryness. The residue was purified bycolumn chromatography (silica gel, CHCl_(3/)Et₂O). The pure fractionswere collected and the solvent was evaporated. The residue wascrystallized from hexane/Et₂O (1/1) to give (100%) compound (A1).

The following compounds were prepared according to the procedure above:

Compound (A23): TFA (1 g, 8.8 mmol) was added to a solution ofintermediate (G5) (0.50 g, 1.0 mmol) in dry DCM (50 mL). The reactionmixture was stirred at RT for 6 hours. The mixture was neutralized withNa2CO3 and washed with water. The organic layer was separated, driedover sodium sulfate, filtered and evaporated till dryness. The residuewas taken up in hexane, the solid was filtered off and dried to give0.38 g (96%) of compound (A23).

Compound (A24): TBTU (100 mg, 0.3 mmol) was added to a mixture ofintermediate (E22) (110 mg, 0.3 mmol), 2-methylazepane hydrochloride (44mg, 0.3 mmol) and DIEA (0.15 mL, 0.9 mmol) in DCM (2 mL). The reactionmixture was stirred at RT overnight. The reaction mixture was pouredinto water. The organic layer was separated, washed with brine, driedover sodium sulfate, filtered and evaporated. The residue was purifiedby column chromatography (silica gel, DCM). The pure fractions werecollected and the solvent was evaporated to give 23 mg (18%) of compound(A24).

The following compounds were prepared according to the above procedure:

Compound (A32): Selectfluor® (0.5 g, 1.4 mmol) was added to a solutionof compound (A4) (0.265 g, 0.7 mmol) in CH₃CN (20 mL). The reactionmixture was stirred at RT for 24 h, then aqueous solution of NaHCO3 (90mg) was added and the reaction mixture was stirred for 1 hour. Thereaction mixture was extracted with DCM (2×50 mL). The combined organiclayers were washed with water, dried over sodium sulfate and evaporatedtill dryness. The residue was purified by HPLC to give 23 mg (9%) ofcompound (A32).

Compound (B)

Compound (B1): 2-(isocyanatomethyl)tetrahydrofuran (120 mg, 0.95 mmol)was added to a solution of intermediate (G45) (250 mg, 0.6 mmol) inCH₃CN (5 mL). The reaction mixture was stirred at RT overnight. Thereaction mixture was evaporated and the residue was purified byre-crystallization from EtOAc/hexane to give 270 mg (87%) of compound(B1).

The following compounds were prepared according to the above procedure:

Compound (B5): 2-(isocyanatomethyl)tetrahydrofuran (52 mg, 0.41 mmol)was added to a mixture of intermediate (G54) (150 mg, 0.41 mmol) inCH₃CN (1 mL). The reaction mixture was stirred at RT overnight. Thereaction mixture was evaporated and the residue was purified by columnchromatography (silica gel, DCM/EtOAc (8/1)). The pure fractions werecollected and the solvent was evaporated to give 43 mg (32%) of compound(B5).

The following compounds were prepared according to the above procedure:

Compound (B10): 2-(isocyanatomethyl)tetrahydrofuran (84 mg, 0.66 mmol)was added to a solution of intermediate (G47) (0.250 g, 0.60 mmol) indry THF (25 mL). The reaction mixture was stirred at RT for 6 hours. Themixture was poured into water and extracted with EtOAc. The organiclayer was separated, washed with water, dried over sodium sulfate andevaporated till dryness. The residue was purified by HPLC to give (22%)compound (B10).

The following compounds were prepared according to the above procedure:

Compound (B13): Thiophosgene (58 mg, 0.5 mmol) was added at 0° C. to amixture of intermediate (G45) (0.2 g, 0.5 mmol) and DIEA (0.25 mL, 1.5mmol) in DCM (5 mL). The reaction mixture was stirred for 15min. Then(tetrahydrofuran-2-ylmethyl)amine (60 mg, 0.6 mmol) was added and thereaction mixture was stirred at RT overnight. A saturated aqueoussolution of NaHCO₃ was added and the organic layer was separated, washedwith brine, dried over sodium sulfate, filtered and evaporated tilldryness. The residue was purified by column chromatography (silica gel,DCM/EtOAc). The pure fractions were collected and the solvent wasevaporated to give 250 mg (92%) of compound (B13).

The following compounds were prepared according to the above procedure

Compound (B16): Cyanamide (10 mg, 0.2 mmol) was added to a mixture ofcompound (B13) (100 mg, 0.2 mmol), EDC (53 mg, 0.3 mmol) and Et₃N (0.1mL, 0.74 mmol) in CH₃CN (5 mL). The reaction mixture was stirred at 80°C. overnight. The solvent was evaporated, then the residue was taken upin EtOAc and washed with water. The organic layer was separated, washedwith brine, dried over sodium sulfate, filtered and evaporated tilldryness. The residue was purified by column chromatography (silica gel,DCM/EtOAc). The pure fractions were collected and the solvent wasevaporated to give 40 mg (43%) of compound (B16).

The following compounds were prepared according to the above procedure

Compound (C)

Compound (C1): Triphosgene (23 mg, 0.03 mmol) was added at 0° C. to amixture of intermediate (G45) (120 mg, 0.3 mmol) and DIEA (0.15 mL, 0.9mmol) in DCM (1 mL). The reaction mixture was stirred for 15 min. Thentetrahydrofuran-2-ylmethanol (35 mg, 0.33 mmol) was added and thereaction mixture was stirred at RT overnight. A saturated aqueoussolution of NaHCO₃ was added and the organic layer was separated, washedwith brine, dried over sodium sulfate, filtered and evaporated tilldryness. The residue was purified by column chromatography (silica gel,DCM/EtOAc). The pure fractions were collected and the solvent wasevaporated to give 0.94 g (60%) of compound (C1).

The following compounds were prepared according to the above procedure:

Compound (C6): Triphosgene (47 mg, 0.16 mmol) was added at 0° C. to amixture of intermediate (G54) (0.2 g, 0.53 mmol) and DIEA (0.205 g, 1.59mmol) in DCM (20 mL). The reaction mixture was stirred for 15 min. Thenethylene glycol (36 mg, 0.58 mmol) was added and the reaction mixturewas stirred at RT for 6 hours. A saturated aqueous solution of NaHCO₃was added and the organic layer was separated, washed with brine, driedover sodium sulfate, filtered and evaporated till dryness. The residuewas purified by column chromatography (silica gel, DCM/EtOAc). The purefractions were collected and the solvent was evaporated to give (41%)compound (C6).

The following compound was prepared according to the above procedure:

Compound (D)

Compound (D1) and (D′1): Methanesulfonyl chloride (22 mg, 0.27 mmol) wasadded to a mixture of intermediate (G45) (100 mg, 0.27 mmol) and Et₃N(0.04 mL, 0.27 mmol) in DCM (1 mL). The reaction mixture was stirred atRT overnight. A saturated aqueous solution of NaHCO₃ was added and theorganic layer was separated, washed with brine, dried over sodiumsulfate, filtered and evaporated till dryness. The residue was purifiedby column chromatography (silica gel, DCM/EtOAc). The pure fractionswere collected and the solvent was evaporated to give (34%) compound(D′1) and (24%) compound (D1).

The following compounds were prepared according to the above procedure:

Compound (E)

Compound (El): TBTU (0.90 g, 0.27 mmol) was added to a mixture ofintermediate (G45) (0.1 g, 0.25 mmol) with1-methyl-1H-imidazole-2-carboxylic acid (0.40 g, 0.27 mmol) and DIEA(0.65 mL, 0.39 mmol) in DCM (5 mL). The reaction mixture was stirred atRT overnight. The reaction mixture was poured into water. The organiclayer was separated, washed with brine, dried over sodium sulfate,filtered and evaporated till dryness. The residue was purified by columnchromatography (silica gel, DCM). The pure fractions were collected andthe solvent was evaporated to give 97 mg (76%) of compound (E1).

The following compounds were prepared according to the above procedure:

Compound (E10): Cyclopropanecarbonyl chloride (110 mg, 0.55 mmol) wasadded to a mixture of intermediate (G46) (200 mg, 0.5 mmol) and Et₃N(0.1 mL, 0.55 mmol) in DCM (5 mL). The reaction mixture was stirred atRT overnight. A saturated aqueous solution of NaHCO₃ was added and theorganic layer was separated, washed with brine, dried over sodiumsulfate, filtered and evaporated till dryness. The residue was purifiedby re-crystallization from EtOAc/ether to give 145 mg (63%) of compound(E10).

The following compounds were prepared according to the above procedure:

Compound (E17): Cyclopropylcarbonyl chloride (70 mg, 0.66 mmol) wasadded to a solution of intermediate (G47) (0.250 g, 0.60 mmol) in dryTHF (25 mL) and DIEA (0.114 mL, 0.66 mmol). The reaction mixture wasstirred at RT for 6 hours. The mixture was poured into water andextracted with EtOAc. The organic layer was separated, washed withwater, dried over sodium sulfate, filtered and evaporated till dryness.The residue was purified by HPLC to give (45%) compound (E17).

The following compounds were prepared according to the above procedure:

Compound (E20): Propylcarbonyl chloride (57 mg, 0.53 mmol) was added toa solution of intermediate (G54) (0.200 g, 0.53 mmol) and DIEA (0.091mL, 0.53 mmol) in dry THF (25 mL). The mixture was stirred at RT for 6hours. The mixture was poured into water and extracted with EtOAc. Theorganic layer was washed with water, dried over sodium sulfate, filteredand evaporated till dryness. The residue was purified by columnchromatography then crystallized from Et₂O to give (56%) compound (E20).

Compound (E21): Prepared according to the above procedure fromintermediate (G54) and propen-2-carbonyl chloride.

Compound (E22): 1-methyl-1H-imidazole-2-carboxylic acid (67 mg, 0.53mmol) was added to a solution of intermediate (G54) (0.200 g, 0.53mmol), DIEA (0.40 mL, 2.3 mmol) and BOP (0.786 g, 1.7 mmol) in dry DMF(15 mL). The reaction mixture was stirred at RT for 6 hours. The mixturewas poured into water and extracted with EtOAc. The organic layer waswashed with water, dried over sodium sulfate, filtered and evaporatedtill dryness. The residue was purified by column chromatography thencrystallized from Et₂O to give (24%) compound (E22).

Compound (E23): Prepared according to the above procedure fromintermediate (G54) and pyridin-4-ylacetic acid.

Reaction scheme:

Compound (E24): KOH (100 mg, 1.96 mmol) was added to a stirred solutionof intermediate (G50) (500 mg, 0.98 mmol) in EtOH (5 mL). The reactionmixture was stirred at RT for 1 hour. The solvent was evaporated, thenthe residue was taken up in water and washed with ether. The aqueouslayer was neutralized with HCl cc (0.2 mL) to pH 7. The precipitate wasfiltered off and dried to give 480 mg (100%) of compound (E24).

Compound (E25) and (E26): TBTU (90 mg, 0.28 mmol) was added to a mixtureof compound (E24) (150 mg, 0.3 mmol), NH₄Cl (100 mg, 1.3 mmol) and DIEA(0.25 mL, 1.3 mmol) in DCM (5 mL). The reaction mixture was stirred atRT overnight. The reaction mixture was poured into water. The organiclayer was separated, washed with brine, dried over sodium sulfate,filtered and evaporated till dryness. The residue was purified by columnchromatography (silica gel, DCM/EtOAc). The pure fractions werecollected and the solvent was evaporated to give 32 mg (21%) of compound(E25) and 66 mg (46%) of compound (E26).

The following compounds were prepared according to the above procedure:

Compound (E30): Cyclopropylcarbonyl chloride (50 mg, 0.47 mmol) wasadded to a solution of compound (A23) (0.150 g, 0.43 mmol) and DIEA(0.081 mL, 0.47 mmol) in dry THF (25 mL). The reaction mixture waspoured into water. The organic layer was separated, washed with brine,dried over sodium sulfate, filtered and evaporated till dryness. Theresidue was purified by HPLC to give (64%) compound (E30).

Compound (F) and (G)

Compound (F1): A mixture of intermediate (G3) (0.47 mmol), 4-pyridineboronic acid (0.51 mmol), Cs₂CO₃ (0.107 g, 10 mmol) and Pd(PPh₃)₄(0.012g, 0.01 mmol) in 1,4-dioxane (19 mL) and water (1 mL) under argon washeated at 130° C. for 4 h using one single mode microwave (Biotage) witha power output ranging from 0 to 400 W. The solvent was evaporated andthe mixture was taken up in CHCl₃ and water. The organic layer wasseparated, washed with water, dried over sodium sulfate, filtered andevaporated till dryness. The residue was purified by columnchromatography (silica gel, CHCl_(3/)Et₂O (1/1)). The pure fractionswere collected and the solvent was evaporated to give (41%) compound(F1).

The following compounds were prepared according to the above procedure:

Compound (F4): A mixture of intermediate (G2) (0.100 g, 0.22 mmol),Cs₂CO₃ (0.156 g, 4.36 mmol), Pd(PPh₃)₄ (23 mg, 0.02 mmol) and 3-pyridineboronic acid (32 mg, 0.26 mmol) in 1,4-dioxane (20 mL) and water (1 mL)was heated at 150° C. for 2 hours using one single mode microwave(Biotage®) with a power output ranging from 0 to 400 W. The solvent wasevaporated and the mixture was taken up in CHCl₃ and water. The organiclayer was separated, washed with water, dried over sodium sulfate,filtered and evaporated till dryness. The residue was purified by columnchromatography to give (28%) the compound (F4).

Compound (FS): A mixture of intermediate (G2) (0.100 g, 0.22 mmol),Cs₂CO₃ (0.156 g, 4.36 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol) and1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(73 mg, 0.26 mmol) in 1,4-dioxane (20 mL) and water (1 mL) was heated at150° C. for 2h using one single mode microwave (Biotage®) with a poweroutput ranging from 0 to 400 W. The solvent was evaporated and themixture was taken up in CHCl₃ and water. The organic layer wasseparated, washed with water, dried over sodium sulfate, filtered andevaporated till dryness. The residue was purified by columnchromatography and after then the product was stirred in a mixture ofTHF and HCl cc (1/1) at RT for 4 hours. The reaction mixture wasevaporated till dryness and the residue was purified by HPLC to give(86%) compound (F5).

The following compound was prepared according to the above procedure:

Typical procedure for the synthesis of compounds (F) via intermediate(G29): Intermediate (G29) (0.250 g, 0.49 mmol), Na2CO₃(0.115 g, 1.08mmol), Pd(PPh3)4 (56 mg, 0.05 mmol) and the corresponding halide (0.54mmol) was dissolved in 1,4-dioxane (20 mL) and water (1 mL). Thereaction mixture was heated at 150° C. for 2 h using one single modemicrowave (Biotage®) with a power output ranging from 0 to 400 W. Thecrude product was purified by column chromatography or HPLC.

The following compounds were prepared according to the above procedure:

Compound (F15)

Intermediate (G316): A solution of intermediate (G30) (7.5 g, 14.81mmol) and ethyl 6-chloronicotinate (5.50 g, 29.62 mmol) in K₂CO₃(9.48mL, 2 M, 18.96 mmol) and Me-THF (36 mL) was degased with nitrogen for 10min. PdCl2(dppf)DCM (1.21 g, 1.48 mmol) was added and the mixture washeated at 120° C. using a singlemode microwave (Anton Paar®

Monowave 300) with a power output ranging from 0 to 850 W for 30min. Thereaction mixture was filtered through a short pad of Celite®, the cakewas washed with EtOAc, the organic layer was separated, washed withbrine, dried (MgSO₄) and evaporated till dryness. Purification of theresidue was carried out by flash chromatography over silica gel(cartridge 180 g, 15-40 μm, Heptane/EtOAc 80/20). The pure fractionswere collected and evaporated to dryness to afford 4.3 g (55%) ofintermediate (G316).

A mixture of intermediate (G312) (4.3 g, 8.12 mmol) and KOH (0.68 g,12.18 mmol) in EtOH (45mL) was stirred at reflux for 1 h30. The mixturewas cool down to RT and evaporated till dryness. The residue was takenup in water (75mL), HCl 3M (4.06 mL, 3 M, 12.18 mmol) was added, thegel-like mixture was filtered, taken up in CH₃CN, stirred 1 hour,filtered and dried under vacuum to afford 3.1 g of compound (F15).

Compound (F18): Intermediate (G29) (0.2 g, 0.4 mmol), Na₂CO₃(0.130 g,1.2 mmol), PdCl₂(PPh₃)₂ (5% mol) and2-bromo-4-methyl-1,3-thiazole-5-carboxylic acid (90 mg, 0.4 mmol) wasdissolved in 1,4-dioxane (1 mL) and water (1 mL). The reaction mixturewas heated at reflux for 5 hours. Then, the solution was filtered toremove the precipitate and the filtrate was evaporated. DCM and waterwere added to the residue and the organic layer was separated. Theaqueous layer was acidified HCl cc to pH 3. The mixture was extractedwith DCM. The organic layers were combined, dried over sodium sulfate,filtered and the solvent was evaporated. The residue was recrystallizedwith EtOAc to give 30 mg (15%) of compound (F18).

Compound (F26): In a sealed tube, a solution of intermediate (G77) (421mg; 0.613 mmol), intermediate (S3) (165 mg; 0.613 mmol) and K₃PO₄ (391mg; 1.84 mmol) in 1.4dioxane (8 mL) and H₂O (1.2 mL) was purged with Nz.PdClz(dtbpf) (40 mg; 61 μmol) was added, the mixture was purged againwith Nz and heated at 80° C. using one single mode microwave (Biotage®Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. The mixture was evaporated in vacuum to give a brown solid which waspurified by column chromatogeraphy (silica gel, from DCM/MeOH/AcOH100/0/0 to 95/5/0.5), the pure fractions were collected and evaporatedto give a solid. The solid was triturated in MeOH, filtered, washed withMeOH and dried under high vacuum (50° C., 2 hours) to afford 202 mg(69%) of compound (F26).

The following compounds were prepared according to the above procedure.

Compound (F33): A solution of intermediate (G77) (492 mg; 0.716 mmol,60% purity), 6-bromo-7-fluoro-2-Quinolinecarboxylic acid CAS[1598112-25-4] (193 mg; 0.716 mmol) and K₃PO₄ (456 mg; 2.15 mmol) indioxane (9.7 mL) and H₂O (3.0 mL) was purged by Nz bubbling for 10 minbefore the addition of Pd118 (47 mg; 71 μmol). The resulting mixture waspurged by N₂ bubbling, then heated at 80° C. using one single modemicrowave (Biotage^(R) Initiator EXP 60) with a power output rangingfrom 0 to 400 W for 30 min [fixed hold time]. The crude was evaporateduntil dryness and purified by preparative LC (Regular SiOH 30 μm, 25 gInterchim®, dry loading (Celite®), mobile phase gradient: fromCH₂Cl₂/MeOH/AcOH 100:0:0 to 90:10:1) to give 147 mg of impure compoundwhich was purified again by preparative LC (Regular SiOH 30 μm, 4 gInterchim®, dry loading (Celite®), mobile phase gradient: fromCH₂Cl₂/MeOH 100:0 to 95:5) to give 90 mg (26%) of compound (F33) as anoff-white solid.

Reaction scheme:

Compound (F19): A mixture of intermediate (G64) (0.18 g, 0.34 mmol) andLiOH.H₂O (0.03 g, 0.67 mmol) in THF (3.6 mL, 44.1 mmol) and H₂O (0.3 mL)was stirred at 60° C. for 2 hours. The mixture was evaporated, theresidue was taken up in water, acidified with HCl 3M (0.56 mL, 1.68mmol), filtered and dried till dryness under vacuum (60° C.) to give 152mg (87%) of compound (F19).

The following compounds were prepared according to the above procedure:

Compound (F22): A mixture of intermediate (G71) (0.085 g, 0.155 mmol)and KOH (0.043 g, 0.77 mmol) in EtOH (5mL) was stirred at reflux for 1hour The mixture was cooled down to RT and evaporated till dryness. Theresidue was taken up in water, HCl (3M in H₂O) (0.26 mL, 0.77 mmol) wasadded, the gel-like mixture was filtered, the solid was washed withwater and dried (vacuum, 60° C.) to give 0.053g, (64%) of compound(F22).

The following compound was prepared according to the above procedure:

Compound (F29): LiOH.H₂O (131 mg; 3.12 mmol) was added to a solution ofintermediate (G90) (317 mg; 0.624 mmol) in THF (4.5 mL) and water (1.5mL). The reaction mixture was stirred at RT for 16 hours. Then asolution of HCl 3M in CPME (1 mL; 3.12 mmol) was added and the reactionmixture was concentrated to give crude product which was purified bycolumn chromatography (silica gel, from DCM/MeOH 100/0 to 80/20). Thepure fractions were collected and evaporated to give a yellow solid. Thesolid was triturated in hot acetonitrile, filtered and dried under highvacuum (50° C., 18 hours) to give 143 mg (48%) of compound (F29) as ayellow solid.

The following compound was prepared according to the above procedure:

Compound (F36)

Intermediate (G105): In a sealed tube, a solution of intermediate (G77)(500 mg; 0.84 mmol), intermediate (S8) (305 mg; 0.87 mmol) and K₃PO₄(594 mg; 2.8 mmol) in 4-dioxane (10 mL) and H₂O (1.6 mL) was purged withN₂. PdCl₂(dtbpf) (55 mg; 84 μmol) was added, the mixture was purgedagain with Nz and heated at 80° C. using a single mode microwave(Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 Wfor 30 min [fixed hold time]. Water and EtOAc were added. The layerswere separated. The organic layer was dried over MgSO₄, filtered andconcentrated. This mixture was purified by preparative LC (Regular SiOH,30 μm, 12 g Interchim®, dry loading (on SiOH), mobile phase gradient:from heptane/EtOAc 90/10 to 30/70) to give 374 mg (86%) of intermediate(G105) as a white solid.

b) Compound (F36): LiOH H₂O (123 mg; 2.93 mmol) was added to a solutionof intermediate (G105) (286 mg; 0.58 mmol) in H₂O (1.4 mL) and THF (4.3mL) at rt and the reaction mixture was stirred at rt for 16 h. Then HCl3 M (975 μL; 2.92 mmol) was added dropwise at rt and the reactionmixture was concentrated. It was purified by preparative LC (RegularSiOH, 30 μm, 12 g Interchim®, dry loading (on SiOH), mobile phasegradient: from DCM/EtOH 95/5 to DCM/(EtOH/AcOH 10%) 90/10) to give abeige residue which was taken up in EtOH. The precipitate was filteredand dried under high vacuum at 50° C. for 16 hours to give 187 mg (67%)of compound (F36) as a white solid.

Compound (F37): LiOH.H₂O (23 mg; 0.56 mmol) was added to a solution ofintermediate (G91)(199 mg; 0.372 mmol) in THF (5 mL) and H₂O (2 mL). Themixture was stirred at rt overnight then heated at 50° C. for 3 days.HCl 3M in CMPE (100 μL; 0.3 mmol) was added (until pH=7) and theresulting mixture was stirred at rt overnight. The mixture wasconcentrated until dryness and purified by preparative LC (IrregularSiOH 15-40 μm, 10 g Merck®, dry loading (Celite®), mobile phasegradient: from DCM/MeOH/AcOH 100:0:0 to 95:5:0.5). The fractionscontaining product were combined and the solvent was removed in vacuo togive a yellow oil which was azeotroped with toluene (twice) to give 130mg of a mixture of 2 diastereomers. The mixture was purified via Reversephase (Stationary phase: X-Bridge-C18® 10 μm 30*150 mm, mobile phase:gradient from aq HCOONH₄ (0.6 g/L pH=3.5)/MeCN 60:40 to 0:100) to give24 mg of compound (F37) (13%) as a yellow solid and 56 mg of cis isomer(30%) as a yellow solid.

Compound (F35): In a sealed tube, a mixture of intermediate (G104) (267mg; 0.503 mmol) and LiOH monohydrate (42 mg; 1.0 mmol) in THF (3 mL) andH₂O (1.5 mL) was stirred at rt for 2 days. Brine, an aqueous solution ofKHSO₄ (10%) and EtOAc were added to the reaction mixture, aqueous layerwas extracted with EtOAc (twice). The combined organic layers were driedover MgSO₄, filtered and evaporated in vacuo. The residue was trituratedin DCM and the solid was filtered and dried to give 173 mg (68%) ofcompound (F35) as a white solid.

Compound (F45): A suspension of intermediate (G156) (662 mg; 0.857 mmol)and K₂CO₃ (142 mg; 1.03 mmol) in H₂O (619 μL) and NMP (15 mL) wasdegassed by N₂ bubbling for 15 min before the addition of Pd(OAc)₂ (19mg; 85.7 μmol) and dppp (35 mg; 85.7 μmol). The resulting mixture waspurged with CO (twice) then pressurised with CO (10 bar) and heated at120° C. overnight. Water and EtOAc were added and the mixture wasfiltered through a pad of Celite® and the Celite® was rinsed with a mixof water and EtOAc. The layers were separated and the aqueous layer wasextracted with EtOAc (twice). The aqueous layer was acidified byaddition of aq HCl (3 N) then extracted with EtOAc (twice). The combinedorganic layers were washed with brine (3 times), dried over MgSOt,filtered and concentrated in vacuo. The residue was purified bypreparative LC (Regular SiOH 30 μm, 25 g Interchim®, dry loading(Celite®), mobile phase gradient: from DCM/MeOH 100:0 to 90:10). Thefractions containing product were combined and the solvent was removedin vacuum. Water was added to the residue leading to precipitation, thesolid was filtered off and dried under high vacuum. The solid wassolubilized in a mixture of MeOH/THF (50:50) and then water was added.The mixture was partially evaporated leading to precipitation, theprecipitate was filtered off and dried under high vacuum to give 27 mg(7%) of compound (F45) as an off-white solid.

Compound (G1): HCl cc (0.1 mL) was added to a mixture of intermediate(G29) (0.1 g, 0.2 mmol) in acetone (1 mL). The reaction mixture wasstirred at RT overnight. The precipitate was filtered off, washed withhexane and dried to give 75 mg (90%) of compound (G1).

Compound (H), (I), (J), (K) and (L)

Compound (H) from Bromo by Cyanation:

Compound (I11): Intermediate (G8) (0.72 g, 1.56 mmol), KCN (0.407 g, 6.3mmol), CuI (50 mg) and Pd(PPh₃)₄ (0.360 g, 0.31 mmol) was dissolved indry CH₃CN (25 mL). The reaction mixture was heated at 150° C. for 2 husing one single mode microwave (Biotage®) with a power output from 0 to400 W. The crude product was purified by HPLC to give 325 mg (51%) ofcompound (H1).

The following compound was prepared according to the above procedure:

Compound (H) from Amino Via Diazonium:

Compound (115): Sodium nitrite (0.12 g, 1.74 mmol) in water (4 mL) wasadded dropwise to a suspension of intermediate (G45) (0.54 g, 1.4 mmol),HCl cc (1.7 mL) in water (3.4 mL) and CH₃CN (6.5 mL) at 0° C. Thereaction mixture was stirred at 0° C. for lh until the solid dissolutionthen an aqueous solution of Na₂CO₃ was added till pH 6-7.Simultaneously, a solution of CuSO₄,5H20 (0.45 g, 1.8 mmol) in water (2mL) was added dropwise to a solution of KCN (0.45 g, 6.9 mmol) in water(3 mL) at 0° C. Toluene (6 mL) was then added and the reaction mixturewas heated at 60° C. for 1 hour. The diazonium salt solution was addeddropwise over 15 min to this copper cyanide mixture at 60° C. Thereaction mixture was heated at 70° C. for 1.5 h, allowed to cool down toRT, partitioned between EtOAc and water and the aqueous layer wasextracted with EtOAc (×3). The combined organic extracts were dried withsodium sulfate, filtered and evaporated. The solid was purified bycolumn chromatography (silica gel, DCM/EtOAc (5/1)). The pure fractionswere collected and the solvent was evaporated to give 0.28 g of compound(H5).

Compound (H): TBTU (0.05 g, 0.33 mmol) was added to a mixture ofintermediate (E2) (0.1 g, 0.3 mmol), (2R)-2-methylazepane hydrochlorideCAS ([331994-00-4], 0.045 g, 0.3 mmol) and DIEA (0.15 mL, 0.9 mmol) inDCM (1 mL). The reaction mixture was stirred at RT overnight. Thereaction mixture was poured into water. The organic layer was separated,washed with brine, dried over sodium sulfate, filtered and evaporatedtill dryness. The residue was purified by column chromatography (silicagel, DCM). The pure fractions were collected and the solvent wasevaporated to give 76 mg (61%) of compound (I1).

The following compounds were prepared according to the above procedure:

The following compounds were prepared according to compounds (I1):

Compound (127): A mixture of intermediate (G57) (120 mg, 0.28 mmol) inTFA/H₂SO₄ (2.5 mL, 4/1) was stirred at RT for 48 hours. The reactionmixture was diluted with water and a precipitate was filtered off,washed with water and dried to give 116 mg (93%) of compound (127).

The compound (128) was also prepared according to the above procedure.

Compound (J1): Compound (I) (0.2 g, 0.47 mmol) and NaHCO₃ (0.04 g, 4.8mmol) were suspended in CH₃CN (5 mL) and heated at 60° C. A solution ofSelectfluor® reagent (0.334 g, 0.94 mmol) in CH₃CN (3 mL) was addeddropwise during 1.5 h to the previous mixture. The reaction mixture wasstirred at that temperature for another hour and cooled to RT. Thesolution was diluted with EtOAc and washed with water. The organic layerwas separated, dried over sodium sulfate, filtered and evaporated tilldryness. The residue was purified by column chromatography to give 29 mgof compound (J1).

The compound (J2) was also prepared according to the above procedure.

Compound (K1): A mixture of compound (I) (100 mg, 0.22 mmol) in HCl cc(1 mL) was heated at reflux for 2 hours. The reaction mixture was pouredinto water and the resulting suspension was filtered. The precipitatewas washed with water and dried to give 40 mg (40%) of compound (K1).

Compound (K2): A mixture of compound (I) (200 mg, 0.47 mmol) in HCl cc(2 mL) was heated at reflux for 2 hours. The reaction mixture was pouredinto water and the resulting suspension was filtered. The precipitatewas washed with water and dried to give 160 mg (80%) of compound (K2).

The compounds (K3) to (K9) were prepared according to the aboveprocedure:

Compound (L1): Compound (K2) (90 mg, 0.21 mmol), TBTU (0.31 mmol), DIEA(0.1 mL) and cyclopropylamine (0.26 mmol) were dissolved in DCM. Thereaction was stirred at RT for 2 hours. The reaction mixture was pouredinto water and the organic layer was separated, washed with water, driedover sodium sulfate, filtered and evaporated till dryness. The residuewas purified by column chromatography to give (78%) compound (L1).

The compounds (L2) to (L9) were prepared according to the aboveprocedure.

Compound (L10): Compound (K2) (0.1 g, 0.24 mmol), TBTU (0.1 g, 0.31mmol), DIEA (0.12 mL), methanesulfonamide (0.03 g, 0.32 mmol) and DMAP(0.1 g, 0.82 mmol) were dissolved in DCM. The reaction mixture wasstirred at RT overnight. The reaction mixture was poured into water andthe organic layer was separated, washed with water, dried over sodiumsulfate, filtered and evaporated till dryness. The residue was purifiedby column chromatography to give 0.65 g of compound (L10).

Reaction scheme:

Compound (L11): KOH (26 mg, 0.4 mmol) was added to a solution ofintermediate (G59) (100 mg, 0.19 mmol) in EtOH. The reaction mixture wasstirred at RT overnight. The mixture was poured into water and acidifiedwith HCl to pH 3. The precipitate was filtered off, washed with waterand dried to give 56 mg (56%) of compound (L11).

Compound (I) from Cyano (H) by Acidic Hydrolysis

Compound (I29): A solution of compound (H1) (0.150 g, 0.37 mmol) in amixture of TFA/H₂SO₄ (4/1) (15 mL) was stirred at RT for 24 hours. Themixture was poured into water and the precipitate was filtered off anddried to give 80 mg (51%) of compound (129).

The following compounds were prepared according to the above procedure:

Compound (I) from Cyano (H) by Basic Hydrolysis

Compound (I32): Compound (H3) (0.1 g, 0.23 mmol) was dissolved in MeOH,hydrogen peroxide 35% (0.025 mL, 0.025 mmol) and NaOH (5%, 0.1 mL) wereadded and the reaction mixture was stirred at 40° C. for 4 hours. Waterwas added and the precipitate was filtered off to give 55 mg (50%) ofcompound (I32).

Compound (M) and (N)

Compound (M1): KOH (40 mg, 7.1 mmol) was added to a stirred solution ofintermediate (G31) (170 mg, 3.6 mmol) in EtOH (5 mL). The reactionmixture was stirred at RT for 1 hour. The solvent was evaporated and theresidue was poured into water and extracted with ether. The organiclayer was separated and the aqueous one was acidified with HCl cc (0.1mL) to pH 3. The precipitate was filtered off and dried to give 150 mg(94%) of compound (M1).

The compounds (M2) to (M13) were prepared according to the aboveprocedure.

The following compounds were prepared according to compounds (M1):

Compound (M14): A mixture of intermediate (G61) (0.35 g, 0.68 mmol) andLiOH.H₂O (57.2 mg, 1.36 mmol) in THF (2 mL), MeOH (2 mL) and H₂O (0.1mL) was stirred at 60° C. for 1 hour. The mixture was cooled down to RT,the solvents were evaporated, the residue was taken up in few H₂O andHCl (3M in H₂O)(0.45 mL, 1.36 mmol) was added. The aqueous layer wasseparated extracted with CH₂Cl₂ and MeOH (50/50), dried over MgSO₄ andevaporated till dryness, crystallized from EtOH, filtered and dried toafford 220 mg of a residue which was purified by column chromatography(silica gel, from 98/2 to 95/5 CH₂Cl₂/MeOH). The pure fractions werecollected and evaporated to dryness to afford 170 mg of an intermediatewhich was crystallized in EtOH, filtered and dried under vacuum (50°C.). This compound and the mother layer were purified via achiral SFC(Stationary phase: CYANO® 6 μm 150×21.2 mm, Mobile phase: 70% CO₂, 30%EtOH(0.3% iPrNH₂). The good fractions were collected and the solvent wasevaporated to afford 150 mg of a crude product which was crystallized inEt₂O, filtered and dried under vacuum (50° C.) to afford of anintermediate that was washed with DCM and 1 ml of HCl 1N, filtered on anhydrophobic frit, evaporated till dryness, taken up in Et₂O, filteredand dried under vacuum to afford 78 mg (24%) of compound (M14).

Reaction scheme:

Compound (M15): A solution of intermediate (G62) (0.73 g, 1.48 mmol) inCH₃CN (8 mL) was degassed with nitrogen for 10 min. Acrylic acid (0.2mL, 2.96 mmol), Pd(OAc)₂ (0.033 g, 0.15 mmol), tri-o-tolylphosphine(0.067 g, 0.22 mmol) and Et₃N (0.42 mL, 2.96 mmol) were added and themixture was heated at 120° C. using a singlemode microwave(BiotageOinitiator60) with a power output ranging from 0 to 400 W for 20min. The reaction mixture was filtered through a short pad of Celite®,washed with DCM, water and HCl (3M in H₂O) was added to the filtrate,the organic layer was separated (hydrophobic frit) and evaporated toafford 980 mg of a residue. Purification of the residue was carried outby flash chromatography (silica gel, DCM/MeOH 97/3). The pure fractionswere collected and evaporated to dryness to afford 610 mg of the goodcompound. This compound was crystallized in CH₃CN, filtered and driedunder vacuum (50° C.) to afford 352 mg (49%) of (M15).

The following compounds were prepared according to the above procedure.

Compound (M16): A solution of intermediate (G63) (0.3 g, 0.56 mmol) inCH₃CN (8 mL) was degased with nitrogen for 10 min. Acrylic acid (0.08mL, 1.12 mmol) , Pd(OAc)₂ (12.60 mg, 0.056 mmol), tri-o-tolylphosphine(25.63 mg, 0.084 mmol) and Et₃N (0.16 mL, 0.72 g/mL, 1.12 mmol) wereadded and the mixture was heated at 120° C. using a singlemode microwave(Biotage® initiator60) with a power output ranging from 0 to 400 W for60 min. The reaction mixture was filtered through a short pad ofCelite®, washed with DCM, water and HCl 3N was added to the filtrate,the organic layer was separated (hydrophobic frit) and evaporated.Purification of the residue was carried out by flash chromatography oversilica gel (Grace Resolve® 24 g, 15-40 nm, DCM/MeOH 97/3). The purefractions were collected and evaporated to dryness. The crude compoundwas taken up in DIPE, filtered and dried under vaccum (50° C.) to afford46 mg (16%) of compound (M16).

Compound (M17): A solution of intermediate (G73) (0.19 g, 0.36 mmol) andLiOH.H₂O (0.030 g, 0.722 mmol) in THF (4 mL) and water (0.4 mL) washeated at 60° C. for 8 hours. The mixture was cooled down to RT, theprecipitate (lithium carboxylate) was filtered off, washed with THF,taken up in water, HCl (3M in H₂O) (0.241 mL, 0.722 mmol) was added andthe precipitate was filtered off, washed with water and dried (60° C.,vacuum) to give 0.066 g (37%) of compound (M17).

Compound (M18): H₂SO₄ (0.060 mL; 1.12 mmol) was added to a solution ofintermediate (G82) (220 mg; 0.397 mmol) in DCM (4 mL). The reactionmixture was stirred at RT overnight (precipitation occured). Thesuspension was partitionned between DCM and water. Layers were separatedand the aqueous layer was extracted with DCM (once). The organic layerwas filtered to give a yellow solid and the filtrate was dried overMgSO₄, filtered and concentrated in vacuum. The solid and the residuewere purified by column chromatography (silica gel, from DCM/MeOH/AcOH100:0:0 to 90:10:1). The pure fractions were collected and the solventwas removed to give a colorless oil, which was azeotroped with toluene(twice). The residue was taken-up in CH₃CN, the solid was filtered anddried in vacuum to give 52 mg (26%) of compound (M18) as a white solid.

Compound (M25): A mixture of intermediate (G81) (223 mg; 0.466 mmol) andLiOHH2O (29 mg; 0.70 mmol) in THF (2.5 mL) and H₂O (1.3 mL) was stirredat RT for 64 hours. HCl 3M in CPME (0.1 mL; 0.3 mmol) was added. Themixture was evaporated to dryness and the residue was purified by columnchromatography (silica gel, from DCM/MeOH/AcOH 100/0/0.1 to 95/5/0.5) togive a gum which was taken-up with CH₃CN. The mixture was evaporated todryness to afford 148 mg (71%) of compound (M25) as an off-white solid.

The following compound was prepared according to the above procedure:

Compound (M27)

a) Intermediate (G318): In a Schlenk tube, a solution of intermediate(G152) (1.46 g; 1.98 mmol; 62%), intermediate (R4) (0.65 g; 2.37 mmol)and K₃PO₄ (1.26 g; 5.93 mmol) in 1,4-dioxane (30 mL) and water (5 mL)was purged with Nz. PdCl₂(dtbpf) (0.13 g; 0.2 mmol) was added, themixture was purged again with N₂ and heated at 80° C. for 2 h.

EtOAc and water were added. The layers were separated and the organiclayer was washed with brine (twice), dried over MgSO₄, filtered andconcentrated to give brown oil. This oil was purified by preparative LC(irregular SiOH 15-40 μm, 50 g Grace Resolv , liquid loading (DCM),mobile phase gradient: from heptane 90%/EtOAc 10% to heptane 50%/EtOAc50%) to give 943 mg (86%) of intermediate (G318) as a pale brownish gum.

b) Compound (M27): LiOH.H20 (0.22 g; 5.14 mmol) was added to a solutionof intermediate (G314) (0.94 g; 1.71 mmol) in water (7 mL) and THF (19mL). The reaction mixture was stirred at rt for 18 h. Brine, aqueoussolution of KHSO₄ (10%) and EtOAc were added to the reaction mixture,aqueous layer was extracted with EtOAc (twice). The combined organiclayers were washed with water/brine 1/1, dried over MgSO₄, filtered andevaporated in vacuum to give a yellowish gum which was triturated inCH₃CN, filtered and dried on frit to give 0.77 g (90%) of compound (M27)as an off-white solid.

Compound (M44): Separation of compound (M43) (1.755 g) was performed viachiral SFC (Stationary phase: Chiralpak AD-H® 5 μm 250*30mm, Mobilephase: 45% CO₂, 55% MeOH). The pure fractions were collected and thesolvent was evaporated to afford 0.88 g of the first enantiomer (*R) asiPrNH₂ salt and 0.948 g of the second enantiomer (*S) as iPrNH₂ salt. Apurification of the first fraction was performed via preparative LC(Stationary phase: irregular 15-40 μm 50 g Merck®, Mobile phase:Gradient from 95% DCM, 5% MeOH to 0.1% H₂O, 90% DCM, 10% MeOH) to give0.73 g (42%). The residue was dissolved in hot EtOH, crystallizationoccurred on standing at rt, the solid was filtered off and dried (60°C., vacuum) to give 0.558 g (32%) of compound (M44).

Compound (M46)

a) Intermediate (D55): A mixture of 2-Butenoic acid,4-cyclopropyl-2-hydroxy-4-oxo-, ethyl ester (11.4 g, 61.89 mmol) and5-bromo-1H-pyrazol-3-amine (12.19 g, 47.61 mmol) in EtOH (90 mL) wasstirred at reflux for 2 h. The mixture was cooled to 5° C. and theprecipitate was filtered off, washed with cold EtOH and dried.Purification was performed via preparative LC (Stationary phase:irregular SiOH 40 μm 200g, Mobile phase: 100% DCM). The good fractionswere collected and the solvent was evaporated to afford 9.4 g (49%) ofintermediate (D55).

b) Intermediate (E56): KOH (10.4 g; 16 mmol) was dissolved in EtOH (340mL) then intermediate (E56) (15.5 g; 52.3 mmol) was added portionwiseand the suspension was stirred at reflux for 4 h. The mixture was cooldown, the precipitate was filtered off, washed with cold EtOH then Et₂Oand dried under vacuum to give 16.5 g (98%) of intermediate (E56) as awhite solid.

c) Intermediate (G257): A mixture of intermediate (E56) (2 g; 6.25mmol), intermediate (F22) (1.15 g; 7.50 mmol), HATU (4.6 g; 12.1 mmol)and DIEA (4.3 mL; 25.0 mmol) in DMF (36 mL) was stirred at rt for 20 h.A sat. aq. solution of NaHCO₃, brine and EtOAc were added to thereaction mixture. The layers were separated. The aqueous layer wasextracted twice with EtOAc. The combined organic layers were washed withbrine (4 times), dried over MgSO₄ and evaporated in vacuum. The crudecompound was purified by preparative LC (irregular SiOH 15-40 μm, 50 gGrace Resolv®, liquid loading (DCM), mobile phase gradient: from heptane90%, EtOAc 10% to Heptane 50%, EtOAc 50%) to give 2.9 g of intermediate(G257) as a yellowish gum.

d) Intermediate (G267): Under N₂, in sealed tube, bispin (2.2 g; 8.66mmol) and KOAc (1.13 g; 11.6 mmol) were added to a solution ofintermediate (G 257) (2.41 g; 5.78 mmol) in 1,4-dioxane (27 mL). Thesolution was purged with nitrogen and charged with PdCl₂(dppf) (473 mg;0.58 mmol). The resulting solution was purged again with nitrogen andstirred at 100° C. for 5 h. EtOAc was added. The organic layer waswashed with water and brine (twice), dried over MgSO4 and concentratedto give 5.14 g of intermediate (G267).

e) Intermediate (G276): A mixture of intermediate (R4) (0.200 g, 0.72mmol), intermediate (G267) (0.52 g, 0.80 mmol at 72 wt % purity), K₃PO₄(0.47 g, 2.2 mmol) and PdCl₂(dtbpf) (0.048 g, 0.07 mmol) in 1,4-dioxane(15 mL) and H₂O (1 mL) was stirred at 90° C. for 1.5 h. The reactionmixture was poured into 30 mL of DCM, washed successively with 15 mL ofwater and 15 mL of brine, dried with Na₂SO₄, filtered and concentratedin vacuum. The crude was purified by column chromatography over silicagel (eluent: DCM/EtOAc 100/0 to 90/10) to give 0.36 g (91%) ofintermediate (G276) as a brownish solid.

f) Compound (M46): LiOHH₂O (80 mg; 1.90 mmol) was added to a solution ofintermediate (G276) (337 mg; 0.64 mmol) in H₂O (1.9 mL) and THF (5.7 mL)and the reaction mixture was stirred at rt for 16 h. Then HCl 3M (0.8mL; 2.4 mmol) was added and the reaction mixture was concentrated togive a beige residue taken up in water and EtOAc. An aqueous solution ofKHSO₄ 10% was added and the layers were separated. The organic layer waswashed with water, dried over MgSO₄, filtered and concentrated to give abeige solid. This solid was triturated in MeOH, filtered and dried overglass frit to give 168 mg (53%) of compound (M46) as a white solid.

Compound (M49): compound (M48) was purified by chiral SFC (Stationaryphase: Chiralpak AS-H® 5 μm 250*20 mm, Mobile phase: 60% CO₂, 40% MeOH)to give 101 mg of 1^(st) diastereomer (Compound (M49)) as a white solidand 103 mg of 2^(nd) diastereomer as a white solid.

Compound (N1): TBTU (75 mg, 1.0 mmol) was added to a mixture of compound(M1) (100 mg, 0.2 mmol), NH₄Cl (50 mg, 1.0 mmol) and DIEA (0.2 mL, 1.0mmol) in DCM (1 mL). The reaction mixture was stirred at RT overnight.The reaction mixture was poured into water, then the organic layer wasseparated, washed with brine, dried over sodium sulfate, filtered andevaporated till dryness. The residue was purified by re-crystallizationfrom EtOAc, washed with hexane and dried to give 22 mg (22%) of compound(N1).

Compound (O)

The following compound was prepared according to the previous describedprocedure.

Compound (O2): LiOH.H₂O (21 mg; 0.498 mmol) was added to a solution ofintermediate (G80) (72 mg; 0.146 mmol) in THF (1 mL) and water (360 μL).The reaction mixture was stirred at 60° C. for 4 h 30 then cooled down.Then HCl 3M in CPME (195 μL; 0.585 mmol) was added and the reactionmixture was concentrated. The residue was purified by columnchromatogarphy (silca gel, from DCM/(EtOH/AcOH 10%) 100/0 to 90/10) togive 50 mg of a solid which was co-evaporated (3×) with a mixture ofDCM/EtOH/CH₃CN then was dried under high vacuum at 50° C. for 16 hoursto give 42 mg (62%) of compound (O2) as a beige solid.

The following compound were prepared according to the above procedure:

Compound (05): In a schlenk tube, NaOH (104 mg; 2.60 mmol) was added toa solution of intermediate (G153) (842 mg; 1.30 mmol) in EtOH (18 mL)and the reaction mixture was stirred at 85° C. for 3 h. A solution ofKHSO₄ 10% was added and the mixture was diluted with EtOAc and water.The layers were separated and the organic layer was washed with brine,dried over MgSO₄, filtered, concentrated and purified by preparative LC(irregular SiOH 15-40 μm, 30 g Grace® Resolv, liquid loading (DCM),mobile phase gradient: from DCM 100%, to DCM 95%, MeOH 5%, then DCM 90%,MeOH/AcOH (90:10) 10%) to give 650 mg of a solid. The solid wastriturated in MeOH, filtered off and dried on frit to give 322 mg of afirst batch of compound (O5) as a beige solid. The mother liquor wasevaporated in vacuum and the residue was triturated in MeOH, filteredand dried on frit to give 120 mg of compound (O5) (second batch) as abeige solid. (Global yield 67%).

The following compounds were prepared according to compound (O5):

Reaction scheme for compound (O6):

Compound (O6): LiOH.H₂O (46 mg; 1.09 mmol) was added to a solution ofintermediate (G171) (367 mg; 0.727 mmol) in THF (7.3 mL) and H₂O (4 mL).The mixture was stirred at rt overnight. Brine and an aqueous solutionof KHSO₄ (10%) were added and the mixture was extracted with EtOAc(twice). The combined organic layers were dried over MgSO₄, filtered andevaporated in vacuum to give 388 mg of a crude mixture. This mixture waspurified by preparative LC (Regular SiOH 30 μm, 25 g Interchim®, liquidloading (CH₂Cl₂), mobile phase gradient: from CH₂Cl₂/MeOH/AcOH 100:0:0to 95:5:0.5). The fractions containing product were combined and thesolvent was removed in vacuum to give colorless oil which was azeotropedwith toluene (twice) then with MeCN (once) to give 254 mg of colorlessoil. This oil was purified via achiral SFC (Stationary phase: Chiralpak®AD-H 5 μm 250*30 mm , mobile phase: CO₂/EtOH 65:35) to give 144 mg of awhite foam (*R,*R) (first diastereomer) and 149 mg of a white foam(*S,*S) (second diastereomer).The first diastereomer was dissolved inMeCN and the solution was extended with distilled water. The resultingmixture was freeze-dried to yield 118 mg (34%) of compound (O6′) (*R,*R)as a white solid. The second diastereomer was dissolved in MeCN and thesolution was extended with distilled water. The resulting mixture wasfreeze-dried to yield 136 mg (39%) of compound (O6) (*S,*S) as a whitesolid.

The following intermediates were prepared according to the aboveprocedure:

Compound (O7): In a sealed tube, NaOH (17.9 mg; 0.446 mmol) was added toa solution of intermediate (G173) (183 mg; 0.298 mmol) in iPrOH (8.6 mL)and H₂O (100 μL). The mixture was stirred at 85° C. for 4 hours. Brineand an aqueous solution of KHSO₄ (10%) were added and the mixture wasextracted with EtOAc (twice). The combined organic layers were driedover MgSO₄, filtered and evaporated in vacuo to give 281 mg of a crudecompound. This compound was purified by preparative LC (Regular SiOH 30μm, 12 g Interchim®, dry loading (Celite®), mobile phase gradient: fromCH₂Cl₂/MeOH 100:0 to 98:2). The fractions containing product werecombined and the solvent was removed in vacuum to give 143 mg of ayellow solid which was taken-up in MeCN, the solid was filtered off anddried under high vacuum to give 101 mg (71%) of compound (O7) as a whitesolid.

Reaction Scheme for Compound (O18):

Compound (O18): H₂SO₄ (96%) (0.28 mL; 5.3 mmol) was added to CrO₃ (318mg; 3.18 mmol) then H₂O (0.31 mL) and acetone (2 mL) were addedsuccessively at 0° C. The resulting mixture was stirred at 0° C. for 5min and this mixture was added to a mixture of Intermediate (G284) (313mg; 0.643 mmol) and acetone (10 mL). iPrOH was added and the mixture wasstirred at rt for 15 min. The resulting mixture was filtered overCelite® and washed with DCM. The filtrate was evaporated to dryness andtaken-up with EtOAc and water. The layers were separated and the aqueouslayer was extracted with EtOAc (once). The combined organic layers werewashed with brine, dried over MgSO₄, filtered and the solvent wasremoved in vacuo. The crude was purified by preparative LC (regularSiOH, 30 μm, 40 g Interchim®, liquid loading (DCM), mobile phasegradient: DCM/MeOH/aqNH3 98/2/0.2 to 95/5/0.5) to give a solid which wastaken-up with EtOH and water and evaporated to dryness. The solid wasdried under high vacuum at 50° C. for 16 h to give 75 mg of Compound(O18).

Reaction Scheme for Compound (O19):

Compound (O19): KOH (55 mg; 0.827 mmol) was added to a solution ofintermediate (G298) (345 mg; 0.551 mmol) in EtOH (5 mL). The reactionmixture was heated at 50° C. for 16 h. The reaction mixture was cooleddown to rt and HCl 3M in CPME (150 μL; 0.45 mmol) was added (pH=6). Thereaction mixture was concentrated. The residue was diluted in a mixtureof THF (4 mL) and H₂O (1 mL) and LiOH.H₂O (13 mg; 0.55 mmol) was added.The reaction mixture was stirred at rt for 56 h. An aqueous solution ofKHSO₄ 10% was added until pH=6. The mixture was diluted with EtOAc andwater. The layers were separated and the organic layer was washed withwater, dried over MgSO₄, filtered, concentrated and purified bypreparative LC (Irregular SiOH, 15-40 μm, 12 g Interchim®, dry loading(on SiOH), mobile phase gradient: from DCM/EtOH 100/0 to 90/10) to givea yellow solid. The solid was purified again by preparative LC(Irregular SiOH, 15-40 μm, 10 g Merck®, dry loading (on SiOH), mobilephase gradient: from DCM/MeOH 100/0 to 80/20) to give 112 mg of amixture of diastereomers after drying under high vacuum at 50° C. as ayellow solid (42%). This mixture was purified via chiral SFC (Stationaryphase: Chiralpak® AS-H 5 μm 250*20 mm, Mobile phase: 60% CO₂, 40% iPrOH)to give 222 mg of 1^(st) diastereomer as salt form as a white foam and215 mg of 2^(nd) diastereomer as salt form as a yellow foam (discarded).

1^(st) diastereomer was taken up with an aqueous solution of KHSO₄ 10%and EtOAc. Layers were separated and the organic layers were washed withwater (twice), dried over MgSO₄, concentrated and dried under highvacuum at 60° C. for 48 h to give 148 mg (27%) of Compound (O19) as awhite solid.

Compound (O20)

a) Intermediate (G277): A mixture of intermediate (R10) (0.200 g, 0.50mmol), intermediate (G267) (0.36 g, 0.56 mmol at 72 wt % purity), K₃PO₄(0.32 g, 1.51 mmol) and PdCl₂(dtbpf) (0.03 g, 0.05 mmol) in 1,4-dioxane(15 mL) and H₂O (1 mL) was stirred at 90° C. for 1.5 h. The reactionmixture was poured into 30 mL of DCM, washed successively with 15 mL ofwater and 15 mL of brine, dried with Na₂SO₄, filtered and concentratedin vacuum. The crude was purified by column chromatography over silicagel (eluent: DCM/EtOAc 100/0 to 90/10) to give 0.207 g (63%) ofintermediate (G277) as brownish solid.

b) Compound (O20): In a sealed tube, NaOH (21 mg; 0.52 mmol) was addedto a solution of intermediate (G277) (167 mg; 0.26 mmol) in EtOH (3.5mL) and the reaction mixture was stirred at 85° C. for 1 h and at rt for17 h. Brine and a solution of HCl 1N were added and the mixture wasdiluted with EtOAc and water. The layers were separated and the organiclayer was washed with brine, dried over MgSO₄, filtered and concentratedto give 114 mg of an orange solid. This solid was triturated in MeCN,filtered and dried on frit to give 97 mg (74%) of compound (O20) as apale orange solid.

Compound (O22): In a screw cap vial, NaOH (36 mg; 0.912 mmol) was addedto a solution of intermediate (G279) (293 mg; 456 μmol) in iPrOH (3.8mL) and H₂O (0.8 mL) at rt. The reaction mixture was stirred at 80° C.for 16 h. The reaction mixture was cooled down to rt and concentrated.An aqueous solution of KHSO₄ 10% was added until pH=6. The mixture wasdiluted with EtOAc and water. The layers were separated and the organiclayer was washed with brine, dried over MgSO₄, filtered, concentratedand purified by preparative LC (irregular SiOH, 15-40 μm, 12 g Grace®Resolv, dry loading (on SiOH), mobile phase gradient: fromDCM/(EtOH-AcOH 10%) 100/0 to 90/10) to give a solid which was driedunder high vacuum at 50° C. for 24 h to give 147 mg (64%) of compound(O22) as a yellow solid.

Reaction Scheme for Compound (O24):

Compound (O24): LiOH.H₂O (8 mg; 0.19 mmol) was added to a solution ofintermediate (G305) (18 mg; 35 μmol) in THF (0.3 mL) and H₂O (0.1 mL).The reaction mixture was stirred at rt for 18 h then at 40° C. for 3days. LiOH.H₂O (8 mg; 0.19 mmol) was added and the mixture was stirredat 50° C. for 2 days. HCl 3M in CPME was added until pH 7. A dry loadingwith Celite® was performed and was purified by preparative LC (sphericalC18 25 μm, 40 g YMC-ODS-25®, dry loading (Celite®), mobile phasegradient: 0.2% aq. NH₄HCO₃/MeCN from 70:30 to 30:70).The fractioncontaining product was freeze-dried to give 15 mg (88%) of compound(O24) as a white solid.

Compound (P)

Compound (P1): Intermediate (G49) (0.17 mmol) was dissolved in EtOAc (1mL) and the solution was cooled to 0° C. Then a large excess ofdimethylamine in THF was added and the reaction mixture was stirred at0° C. for 2 hours. The reaction mixture was poured into water, theorganic layer was separated, washed with brine, dried over sodiumsulfate, filtered and evaporated to give (84%) compound (P1).

The following compounds were prepared according to the above procedure:

Compound (Q) and (R)

Compound (Q1): KOH (40 mg, 7.1 mmol) was added to a solution ofintermediate (G43) (160 mg, 0.33 mmol) in EtOH (5 mL). The reactionmixture was stirred at RT for 1 hour. The solvent was evaporated andwater was added. The mixture was extracted with ether, the organic layerwas separated and the aqueous layer was acidified with HCl cc (0.05 mL)to pH 3. The precipitate was filtered off and dried to give 120 mg (79%)of compound (Q1).

Compound (R1): TBTU (55 mg, 0.17 mmol) was added to a mixture ofcompound (Q1) (70 mg, 0.15 mmol), NH₄Cl (42 mg, 0.8 mmol) and DIEA (0.13mL, 0.8 mmol) in DCM (1 mL). The reaction mixture was stirred at RTovernight. The mixture was poured into water. The organic layer wasseparated, washed with brine, dried over sodium sulfate, filtered andevaporated. The residue was recrystallized with EtOAc, washed withhexane and dried to give 46 mg (66%) of compound (R1).

Compound (S)

Compound (S1): A mixture of intermediate (M2) (0.100 g, 0.36 mmol), BOP(0.181 g, 0.40 mmol), DIEA (71 mg, 0.55 mmol) and 2-methylazepane (45mg, 0.40 mmol) in dry DMF (25 mL) was stirred at RT for 6 hours. Thereaction mixture was poured into water and extracted with CHCl₃. Theorganic layer was separated, washed with brine, dried over sodiumsulfate, filtered and evaporated. The residue was purified by columnchromatography (silica gel, CHCl₃/Et₂O). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom hexane/Et₂O (1/1) to give the racemate compound.

The racemate mixture was separated by chiral column chromatography(Phenomenex Lux® 3 μm 4.5×0.5 Cellulose-1, eluent: heptane/iPrNH2 95/5,22° C.). The pure fractions were collected and the solvent wasevaporated to give compound (S1) (35%, ee 86%).

Compound (T) and (U)

Compound (U1): Triphosgene (23 mg, 0.08 mmol) was added at 0° C. to amixture of intermediate (N2) (100 mg, 0.25 mmol) and DIEA (0.125 mL,0.75 mmol) in DCM (1 mL). The reaction mixture was stirred for 15min.Then (tetrahydrofuran-2-ylmethyl)-amine (28 mg, 0.27 mmol) was added andthe reaction mixture was stirred at RT overnight. A saturated aqueoussolution of NaHCO₃ was added and the organic layer was separated, washedwith brine, dried over sodium sulfate, filtered and evaporated tilldryness. The residue purified by column chromatography (silica gel,DCM/EtOAc). The pure fractions were collected and the solvent wasevaporated to give 42 mg (36%) of compound (U1).

Compound (T1): Cyclopropanecarbonyl chloride (30 mg, 0.28 mmol) wasadded to a mixture of intermediate (N2) (80 mg, 0.2 mmol) and Et₃N (0.04mL, 0.28 mmol) in DCM (1 mL). The reaction mixture was stirred at RTovernight. A saturated aqueous solution of NaHCO₃ was added and theorganic layer was separated, washed with brine, dried over sodiumsulfate, filtered and evaporated till dryness. The residue was purifiedby re-crystallization from EtOAc/ether to give 65 mg (70%) of compound(T1).

Compound (V)

Compound (V1): A mixture of intermediate (N4) (170 mg, 0.42 mmol) inTFA/H₂SO₄ (2.5 mL, 4/1) was stirred at RT for 48 hours. The reactionmixture was diluted with water and the precipitate was filtered off,washed with water and dried to give 100 mg (57%) of compound (V1).

Compound (W):

Compound (W1): A mixture of intermediate (G89) (407 mg, 0.825 mmol) andLiOH.H₂O (52 mg, 1.2 mmol) in THF (17 mL) and H₂O (17 mL) was stirred atRT for 3 hours. HCl 3M in CPME (0.246 mL; 0.739 mmol) was added. Themixture was evaporated to dryness and the residue was purified by columnchromatography (silica gel, from DCM/MeOH/AcOH 99/1/0.1 to 95/5/0.5).The pure fractions were collected and evaporated to give 0.5 g of a gumwhich was taken-up with heptane and DCM. The mixture was evaporated todryness and the solid was dried under high vacuum at 60° C. for 24 hoursto give 240 mg (61%) of compound (W1) as an off-white solid.

The following compounds were prepared according to the above procedure:

Compound (W2)

LiOHH₂O (210 mg; 5.01 mmol) was added to a solution of intermediate(G106) (87 mg; 1.67 mmol) in H₂O (5 mL) and THF (15 mL). The reactionmixture was stirred at 50° C. for 16 h, cooled down to rt. Then HCl 3M(1.7 mL; 5 mmol) was added and the reaction mixture was concentrated.The compound was purified by preparative LC (Regular SiOH, 30 μm, 25 gInterchim®, dry loading (on SiOH), mobile phase gradient: fromDCM/(MeOH/AcOH 10%) 100/0 to 80/20) to give a pale yellow solid. Thiscompound was recrystallized in hot EtOH (20 mL) and the mixture wasconcentrated to dryness to give 783 mg of a pale yellow solid which wasdried under high vacuum to give 586 mg (66%) of compound (W2) as a whitesolid.

Compound (W7)

a) Intermediate (G111): A schlenk tube was charged with intermediate(G1) (1 g; 2.18 mmol), (S)-methyl pyrrolidine-3-carboxylatehydrochloride (433 mg; 2.61 mmol), Cs₂CO₃ (2.13 g; 6.53 mmol) andXantPhos (126 mg; 0.22 mmol) and purged with N₂. 1,4-dioxane (30 mL) wasadded and the mixture was purged again with N₂, then Pd(OAc)₂ (49 mg;0.22 mmol) was added. The reaction mixture was purged with N₂ and heatedat 100° C. for 17 h. The mixture was diluted with EtOAc and water. Thelayers were separated. The aqueous layer was extracted with EtOAc(twice). The combined organic layers were washed with brine, dried withMgSO₄, filtered and the solvent was removed under reduced pressure. Thecrude mixture was purified by prepartive LC (irregular SiOH, 15-40 μm,50 g Grace®, liquid injection (DCM), mobile phase gradient: from Heptane90%, EtOAc 10% to heptane 50%, EtOAc 50%) to give 887 mg (80%) ofintermediate (G111) as a yellow foam.

b) Compound (W7): LiOH.H₂O (213 mg; 5.08 mmol) was added to a solutionof intermediate (G110) (857 mg; 1.69 mmol) in H₂O (7.8 mL) and THF (19mL). The reaction mixture was stirred at rt for 18 h. Brine, an aqueoussolution of KHSO₄ (10%) and EtOAc were added to the reaction mixture,aqueous layer was extracted with EtOAc (twice). The combined organiclayers were washed with water/brine 1/1, dried over MgSO₄, filtered andevaporated in vaccum to give a yellowish gum which was taken up in MeCNand evaporated to give 761 mg (91%) of compound (W7) as a yellow solid.

Compound (W16): To a degassed mixture of intermediate (G1) (300 mg,0.653 mmol), 1-aminocyclopropane-1-carboxylic acid (198.1 mg, 1.95 mmol)and K₂CO₃ (180.5 mg, 1.31 mmol) in DMSO (10 mL) was added successivelyCuI (37.3 mg, 0.196 mmol) at room temperature and the mixture wasdegassed for 5 min with Nz. The resulting mixture was heated at 110° C.for 16 h. Water and DCM were added. The organic layer was separatedthrough a hydrophobic frit and concentrated. Purification was carriedout by flash chromatography (silica gel, Heptane/EtOAc, 90/10) to give168 mg (54%) of compound (W16) as a yellow solid.

Reaction scheme for compound (W19):

Compound (W19): In a sealed tube, a solution of intermediate (G77) (0.05g, 0.079 mmol), intermediate (U1) (0.021 g; 0.079 mmol) and K₃PO₄ (0.05g; 0.24 mmol) in 1,4-dioxane (1 mL) and water (0.14 mL) was purged withNz. PdCl2(dtbpf) (0.005 g; 0.0079 mmol) was added, the mixture waspurged again with N₂ and heated at 80° C. using a single mode microwave(Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 Wfor 30 min [fixed hold time]. Water was added and the aqueous layer wasacidified with HCl 1N. The organic layer was extracted with DCM, driedover MgSO₄, filtered and evaporated to give crude compound. Purificationwas carried out by flash chromatography over silica gel (Grace® Resolv,15-35 μM, 40 g, DCM/MeOH from 100/0 to 95/5). Pure fractions werecollected and evaporated to give oil, 0.189 g. A purification wasperformed via Reverse phase (Stationary phase: YMC-actus® Triart-C18 10μm 30*150 mm, Mobile phase: Gradient from 85% NH₄HCO₃ 0.2%, 15% ACN to45% NH₄HCO₃ 0.2% , 55% ACN). Pure fractions were collected andevaporated to give 0.066 g. This fraction was crystallized from DIPE,filtered off and dried under vacuum at 60° C. affording 0.053 g (20%) ofcompound (W19) as a white powder.

Compound (W21): To a degassed mixture of intermediate (G1) (0.42 g, 0.91mmol), intermediate (U2) (0.22 g, 1.1 mmol) and Cs₂CO₃ (0.89 g, 2.74mmol) in 1,4-dioxane (16.8 mL) was added successively XPhos (0.033 g,0.037 mmol) then Pd₂dba₃ (0.039 g, 0.082 mmol) at room temperature. Theresulting mixture was stirred at 100° C. for 16 h. The solution wascooled down to room temperature and water was added. The mixture wasextracted with EtOAc (twice). The combined organic layers were washedwith brine, dried over MgSO₄, filtered and the solvent was removed invacuum to give yellow oil. Purification was carried out by flashchromatography over silica gel (GraceResolv®, 15-35 μM, 40 g, DCM/MeOHfrom 100/0 to 98/2). Pure fractions were collected and evaporated togive 0.366 g. A purification of the residue was performed viapreparative LC (Stationary phase: irregular bare silica 40 g, Mobilephase: 61% Heptane, 4% MeOH, 35% AcOEt). Pure fractions were collectedand evaporated to give 0.08 g. A purification was performed via Reversephase (Stationary phase: X-Bridge-C18® 10 μm 30*150mm, Mobile phase:Gradient from 60% H₂O, 40% ACN to 0% H₂O, 100% ACN). Pure fractions werecollected and evaporated to give 0.032 g (7%) of Compound (W21) as awhite solid.

Reaction scheme for compound (W38):

Compound (W33)

a) Intermediate (G222): A mixture of intermediate (U5) (0.20 g, 0.64mmol), intermediate (G152) (0.57 g, 0.78 mmol at 63 wt % purity), K₃PO₄(0.41 g, 1.92 mmol) and PdCl₂(dtbpf) (0.04 g, 0.06 mmol) in 1,4-dioxane(15 ml) and water (1 ml) was stirred at 90° C. for 1.5 h under Ar. Thereaction mixture was poured into dichloromethane, washed successivelywith water and brine, dried over Na₂SO₄, filtered and concentrated invacuum. The crude was purified by column chromatography over silica gel(eluent: dichloromethane/EtOAc 100/0 to 90/10) to give 0.27 g (75%) ofintermediate (G222) as yellowish solid.

b) Compound (W33): LiOH.H₂O (0.059 g; 1.40 mmol) was added to a solutionof intermediate (G222) (0.26 g; 0.76 mmol) in water (1.4 mL) and THF(4.2 mL) and the reaction mixture was stirred at rt for 16 h then at 50°C. for 4 h. Then HCl (3M in CPME) (0.6 mL; 1.8 mmol) was added and themixture was concentrated to give a yellow solid. This solid was purifiedby preparative LC (Regular SiOH, 15-30 μm, 12 g Interchim®, dry loading(on SiOH), mobile phase gradient: from heptane/(EtOAc/AcOH 2.5%) 80/20to 20/80) to give a white residue which was taken up in MeOH andconcentrated to give 0.18 g (71%) of compound (W33) as a white solid.

Compound (W37)

a) Intermediate (G289): A screw-cap tube was charged with intermediate(G263) (0.69 g, 1.207 mmol), (S)-methyl pyrrolidine-3-carboxylatehydrochloride CAS [81049-27-6] (0.26 g, 1.45 mmol), Cs₂CO₃ (0.59 g,1.810 mmol), Pd₂dba₃ (0.03 g, 0.03 mmol) and Xantphos (0.04 g, 0.06mmol). The tube was capped with a septum and purged with argon.1,4-dioxane (5 mL) was added via a syringe through the septum. Thereaction flask was sealed and placed in a pre-heated oil bath at 100° C.and stirred for 24 h. The reaction mixture was cooled to roomtemperature and 10 mL of EtOAc were added. The organic layer was washedsuccessively with 5 mL of water and 5 mL of brine, dried with Na₂SO₄,filtered and concentrated in vacuo to give yellow oil. The crude waspurified by column chromatography over silica gel (eluent: DCM/EtOAc,gradient: 100/00 to 90/10) to give 0.15 g (22%) of intermediate (G289)as yellow solid.

b) Compound (W37): LiOH.H₂O (31 mg; 0.73 mmol) was added to a solutionof intermediate (G289) (140 mg; 0.24 mmol) in H₂O (0.7 mL) and THF (2.2mL) and the reaction mixture was stirred at rt for 16 h. An aqueoussolution of KHSO₄ 10% was added and the layers were separated. Theorganic layer was washed with water, dried over MgSO₄, filtered andconcentrated to give yellow oil. This oil was purified by preparative LC(Irregular SiOH, 15-40 μm, 12 g Grace Resolv®, dry loading (on SiOH),mobile phase gradient: from heptane/(EtOAc/AcOH 2.5%) 80/20 to 20/80) togive 95 mg of a yellow sticky oil. It was taken-up in acetonitrile andsonicated (precipitation occurred). The mixture was concentrated to give88 mg (66%) of compound (W37) as a yellow solid.

Compound (W38): LiOH H₂O (38 mg; 0.897 mmol) was added to a solution ofintermediate (G288) (166 mg; 0.292 mmol) in water (1.5 mL) and THF (3.7mL). The reaction mixture was stirred at rt for 18 h. Brine, an aqueoussolution of KHSO₄ (10%) and EtOAc were added to the reaction mixture,aqueous layer was extracted with EtOAc (twice). The combined organiclayers were washed with water/brine 1/1, dried over MgSO₄, filtered andevaporated in vacuo to give a yellowish gum which was taken up in MeCNand evaporated under reduced pressure to give 145 mg of a yellow solid.The compound was triturated in MeCN, filtered off and dried on frit togive 115 mg (73%) of compound (W38) as a yellow solid.

Compound (W41)

a) Intermediate (G278): A mixture of intermediate (U5) (0.22 g, 0.70mmol), intermediate (G267) (0.51 g, 0.8 mmol at 72 wt % purity), K₃PO₄(0.45 g, 2.11 mmol) and PdCl₂(dtbpf) (0.05 g, 0.07 mmol) in 1,4-dioxane(15 mL) and H₂O (1 mL) was stirred at 90° C. for 1.5 h. The reactionmixture was poured into 30 mL of DCM, washed successively with 15 mL ofwater and 15 mL of brine, dried with Na₂SO₄, filtered and concentratedin vacuum. The crude was purified by column chromatography over silicagel (eluent: DCM/EtOAc 100/0 to 90/10) to give 0.398 g (99%) ofintermediate (G278) as brown solid.

b) Compound (W41): LiOH.H₂O (138 mg; 3.29 mmol) was added to a solutionof intermediate (G278) (35 mg; 0.61 mmol) in H₂O (1.5 mL) and THF (5mL). The reaction mixture was stirred at rt for 24 h. Then HCl 3M (1.1mL; 3.3 mmol) was added and the reaction mixture was evaporated andpurified by preparative LC (spherical C18 25 μm, 120 g YMC-ODS-25®, dryloading (celite), mobile phase gradient: 0.2% aq. NH₄+HCO3−/MeOH from80:20 to 30:70 in 15 CV). The pure fractions were collected andconcentrated and extracted with AcOEt and 10% aq. KHSO4. The organiclayer was washed with brine, dried (MgSO₄) and evaporated to give 215 mg(65%) of compound (W41) as a yellow solid.

Compound (W43):

a) Intermediate (G264): A mixture of intermediate (El) (1.04 g; 2.58mmol), intermediate (F22) (538 mg; 2.84 mmol), COMU® (1.66 g; 3.87 mmol;1.5 eq) and DIEA (1.3 mL; 7.54 mmol) in DMF (15 mL) was stirred at rtfor 18 h. The reaction mixture was diluted in ethyl acetate, washed witha sat. aq. solution of NaHCO₃ (twice), brine (3 times), dried over MgSO₄and evaporated in vacuum .The crude compound was purified by preparativeLC (irregular SiOH 15-40 μm, 40 g Grace Resoiv®, liquid loading (DCM),mobile phase gradient: from heptane 90%, EtOAc 10% to Heptane 70%, EtOAc30%) to give 1.04 g (81%) of intermediate (G264) as a pink solid.

b) Intermediate (G290): A sealed tube was charged with intermediate(G264) (478 mg; 0.96 mmol), (S)-methyl pyrrolidine-3-carboxylatehydrochloride (169 mg; 1.18 mmol), Cs₂CO₃ (624 mg; 1.91 mmol) andXantPhos (55 mg; 0.1 mmol) and purged with N₂. 1, 4-dioxane (13 mL) wasadded and the mixture was purged again with N₂, then Pd(OAc)₂ (21 mg;0.1 mmol) was added. The reaction mixture was purged with N₂ and heatedat 100° C. for 17 h. The mixture was diluted with EtOAc and water. Thelayers were separated. The aqueous layer was extracted with EtOAc(twice). The combined organic layers were washed with brine, dried withMgSO₄, filtered and the solvent was removed under reduced pressure. Thecrude compound was purified by prepartive LC (irregular SiOH, 15-40 μm,24 g Grace®, liquid injection (DCM), mobile phase gradient: from Heptane90%, EtOAc 10% to heptane 70%, EtOAc 30%) to give 273 mg (51%) ofintermediate (G290) as a yellow foam.

c) Compound (W43): LiOH H₂O (61 mg; 1.46 mmol) was added to a solutionof intermediate (G290) (273 mg; 0.49 mmol) in H₂O (2.1 mL) and THF (5.5mL). The reaction mixture was stirred at rt for 18 h. Brine, an aqueoussolution of KHSO₄ (10%) and EtOAc were added to the reaction mixture,aqueous layer was extracted with EtOAc (twice). The combined organiclayers were washed with water/brine 1/1, dried over MgSO₄, filtered andevaporated in vacuum to give a yellowish gum which was taken up in MeCNand evaporated to give 237 mg (91%) of compound (W43) as a yellow solid.

Reaction scheme for compounds (W49) and (W50):

Compounds (W49) and (W50): Intermediate (G309) was purified via chiralSFC (Stationary phase: Chiralpak® AD-H 5 μm 250*30 mm, Mobile phase: 55%CO₂, 45% mixture of EtOH/iPrOH 50/50 v/v(+0.3% iPrNH₂)) to give 256 mgof 1^(st) diastereomer as iPrNH₂ salt and 245 mg of 2^(nd) diastereomeras iPrNH₂ salt. 1^(st) diastereomer was taken-up with EtOAc and anaqueous solution of KHSO₄ (10%). The layers were separated and theaqueous layer was extracted with EtOAc (once). The combined organiclayers were dried over MgSO₄, filtered and the solvent was removed invacuo. The product was crystallized (3 times) from MeOH to give 3batches of P^(t) diastereomer. These batches were suspended in water,filtered off and dried over glass frit to give 160 mg of compound (W49).2^(nd) diastereomer was taken-up with EtOAc and an aqueous solution ofKHSO₄ (10%). The layers were separated and the aqueous layer wasextracted with EtOAc (once). The combined organic layers were dried overMgSO₄, filtered and the solvent was removed in vacuo. The product wascrystallized (3 times) from MeOH to give 3 batches of 2^(nd)diastereomer. These batches were suspended in water, filtered off anddried over glass frit to give 202 mg of compound (W50).

Compound (W51)

a) Intermediate (G66): DIEA (2.28 mL, 13.035 mmol) then HATU (2.15g,5.65 mmol) were added to a mixture of (R)-2-methylazepane hydrochloride(0.78 g, 5.21 mmol) and intermediate (E46) (1.8 g, 4.35 mmol) in DMF (50mL) then the mixture was stirred at RT for 3 h. The mixture was pouredout into water dropwise with stirring (20 min), the precipitate wasfiltered off and washed with water. The solid was dissolved in DCM,washed with HCl 1N and water, dried (MgSO₄) and evaporated till drynessto afford 1.75 g (85%) of intermediate (G66).

b) Intermediate (G317): A screw cap tube was charged with intermediate(G66) (0.76 g, 1.61 mmol), (S)-methyl pyrrolidine-3-carboxylatehydrochloride (0.39 g, 1.94 mmol) and cesium carbonate (1.57 g, 4.84mmol) and was purged with N₂. 1,4-dioxane (8 mL) was added and themixture was degased with Nz then palladium acetate (0.036 g, 0.16 mmol)and XantPhos (0.093 g, 0.16 mmol) were added. The reaction mixture waspurged with N₂ and heated at 100° C. for 4 h. An additional amount ofpalladium acetate (0.036 g, 0.161 mmol) and XantPhos (0.093 g, 0.16mmol) were added and the mixture was stirred for 4 h. The reactionmixture was poured out into water and extracted with EtOAc. The mixturewas filtered through a pad of Celite®, the Celite® was rinsed with EtOAcand the organic layer was separated. The aqueous layer was extractedwith EtOAc. The combined organic layers were washed with brine, driedwith MgSO₄, filtered and the solvent was removed under reduced pressureto give a residue (1.1 g). Purification of the residue was carried outby flash chromatography over silica gel (cartridge 40 g, 15-40 μm, fromHeptane/EtOAc 70/30 to 50/50). The pure fractions were collected andevaporated to dryness to give 0.44 g (52%) of intermediate (G317).

Compound (W51): LiOH monohydrate (0.107 g, 2.54 mmol) was added to asolution of intermediate (G313) (0.44 g, 0.847 mmol) in water (0.87 mL)and THF (4.4 mL). The reaction mixture was stirred at rt for 2 h. Themixture was poured out into KHSO₄ (10% aq.) and extracted with DCM. Theorganic layer was separated (hydrophobic frit) and evaporated tilldryness. The residue was crystallized from iPrOH, the precipitate wasfiltered off and dried (60° C., vacuum) to give 0.25 g (60%) of compound(W51).

Compound (Y) (X):

Compound (X1): To a mixture of intermediate (G79) (449 mg; 0.971 mmol)and hydroxylamine hydrochloride (236 mg; 3.40 mmol) in MeOH (8 mL) wasadded KOH (327 mg; 5.83 mmol) and the mixture was stirred at RT for 16hours. Water was added and the mixture was extracted with DCM (once)(DCM organic layer was discarded). The aqueous layer was acidified withan aqueous solution of HCl (solution of 1N in H₂O) and extracted withEtOAc (twice). The combined organic layers (EtOAc) were washed withbrine, dried over MgSO₄, filtered and the solvent was removed in vacuum.The residue was purified by column chromatography (silica gel, fromheptane/EtOAc 80/20 to 0/100). The pure fractions were collected and thesolvent was evaporated to give a yellow solid. This solid was trituratedin CH₃CN, filtered and dried under high vacuum at 50° C. for 16 hours togive 98 mg (22%) of compound (X1) as a yellow solid.

D. Compound Identification NMR

For a number of compounds, NMR spectra were recorded using a BrukerAvance 500 spectrometer equipped with a reverse triple-resonance (¹H,¹³C, ¹⁵N TXI) probe head with z gradients and operating at 500 MHz forthe proton and 125 MHz for carbon; a Bruker DPX 400 spectrometerequipped with a 5 mm reverse triple-resonance (¹H, ¹³C, ¹⁹F BBI) probehead operating at 400 MHz for the proton and 100 MHz for carbon; or aBruker DPX 300 spectrometer equipped with a 5 mm dual probe (¹H, ¹³C,QNP) probe head with z gradients and operating at 300 MHz for the protonand 75 MHz for carbon.

Deuterated solvents were chloroform-d (deuterated chloroform, CDCl₃) orDMSO-d₆ (deuterated DMSO, dimethyl-d6 sulfoxide). Chemical shifts (δ)are reported in parts per million (ppm) relative to tetramethylsilane(TMS), which was used as internal standard.

Compound (B1)

Major rotamer (60%)

¹H NMR (400 MHz, chloroform -d) δ ppm 8.07 (s, 1H) 7.39-7.65 (m, 2 H)6.98-7.11 (m, 1H) 6.72 (s, 1H) 6.18-6.46 (m, 1H) 4.28 (br d, J=12.6 Hz,1H) 4.06-4.11 (m, 1H) 3.73-3.98 (m, 3H) 3.53-3.65 (m, 1H) 2.86-3.32 (m,4 H) 1.57-2.23 (m, 10 H) 1.17-1.51 (m, 9 H)

Minor rotamer (40%)

¹H NMR (400 MHz, chloroform-d) δ ppm 8.07 (s, 1H) 7.39-7.65 (m, 2 H)6.98-7.11 (m, 1H) 6.76 (s, 1H) 6.18-6.46 (m, 1H) 4.68 (br s, 1H)4.06-4.11 (m, 1H) 3.73-3.98 (m, 3H) 3.53-3.65 (m, 1H) 2.86-3.32 (m, 4H)1.57-2.23 (m, 10H) 1.17-1.51 (m, 9H)

Compound (B3)

Major rotamer (80%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.98 (s, 1H) 8.02 (br t, J=8.7 Hz, 1H)7.64 (br d, J=14.8 Hz, 1H) 6.86-7.27 (m, 3H) 6.34 (br s, 1H) 3.55-4.02(m, 6H) 2.95-3.27 (m, 3H) 1.75-2.05 (m, 4H) 1.35-1.70 (m, 12H) 0.97-1.29(m, 5H)

Minor rotamer (20%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.98 (s, 1H) 8.02 (br t, J=8.7 Hz, 1H)7.64 (br d, J=14.8 Hz, 1H) 6.86-7.27 (m, 3H) 6.34 (br s, 1H) 4.43-4.56(m, 1H) 3.55-4.02 (m, 5H) 2.95-3.27 (m, 3H) 1.75-2.05 (m, 4H) 1.35-1.70(m, 12H) 0.97-1.29 (m, 5H)

Compound (C4)

Major rotamer (60%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.15 (br s, 1H) 8.06 (br t, J=8.3 Hz,1H) 7.56 (br d, J=13.6 Hz, 1H) 7.39 (br d, J=8.8 Hz, 1H) 7.01-7.08 (m,2H) 4.78-4.93 (m, 1H) 4.15 (br s, 2H) 3.99 (br d, J=12.5 Hz, 1H)3.36-3.78 (m, 3H) 3.01-3.29 (m, 2H) 2.92 (br t, J=12.5 Hz, 1H) 1.86-2.11(m, 1H) 1.51-1.82 (m, 4H) 1.08-1.43 (m, 9H)

Minor rotamer (40%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.15 (br s, 1H) 8.06 (br t, J=8.3 Hz,1H) 7.56 (br d, J=13.6 Hz, 1H) 7.39 (br d, J=8.8 Hz, 1H) 7.01-7.08 (m,2H) 4.78-4.93 (m, 1H) 4.35-4.52 (m, 1H) 4.15 (br s, 2H) 3.36-3.78 (m,3H) 3.01-3.29 (m, 3H) 1.86-2.11 (m, 1H) 1.51-1.82 (m, 4H) 1.08-1.43 (m,9H)

Compound (D3)

Major rotamer (70%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.25 (s, 1H) 8.11 (br t, J=8.7 Hz, 1H)6.86-7.24 (m, 4H) 3.37-3.84 (m, 3H) 3.24 (q, J=7 .7 Hz, 2H) 3.13 (s, 3H)0.99-2.06 (m, 16H)

Minor rotamer (30%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.25 (s, 1H) 8.11 (br t, J=8.7 Hz, 1H)6.86-7.24 (m, 4H) 4.44-4.58 (m, 1H) 3.37-3.84 (m, 2H) 3.24 (q, J=7 .7Hz, 2H) 3.13 (s, 3H) 0.99-2.06 (m, 16H)

Compound (E2)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.64 (s, 1H, 8.52 (d, J=4.8 Hz, 2H)8.12 (t, J=7.9 Hz, 1H) 7.75-7.85 (m, 1H) 7.40-7.50 (m, 1H) 7.35 (d,J=4.6 Hz, 2H), 6.98-7.15 (m, 2H) 4.00 (br d, J=13.2 Hz, 1H) 3.77 (s, 2H)3.46-3.73 (m, 1H) 3.30-3.50 (m, 2H) 2.91 (br t, J=12.7 Hz, 1H) 0.97-2.12(m, 14H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.64 (s, 1H, 8.52 (d, J=4.8 Hz, 2H)8.12 (t, J=7.9 Hz, 1H) 7.75-7.85 (m, 1H) 7.40-7.50 (m, 1H) 7.35 (d,J=4.6 Hz, 2H), 6.98-7.15 (m, 2H) 4.5-4.60 (m, 1H) 3.77 (s, 2H) 3.52 (brd, J=13.2 Hz, 1H) 3.20-3.50 (m, 3H) 0.97-2.12 (m, 14H)

Compound (E3)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.70 (s, 1H, 8.14 (t, J=8.8 Hz, 1H)7.70-7.80 (m, 1H) 7.67 (s, 1H) 7.40-7.50 (m, 1H) 7.19 (s, 1H, 6.99-7.12(m, 2H) 6.92 (s, 1H, 4.96 (s, 2H) 3.95 (br d, J=13.1 Hz, 1H) 3.60-3.75(m, 1H) 2.85-3.27 (m, 3H) 1.03-2.12 (m, 14H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.70 (s, 1H, 8.14 (t, J=8.8 Hz, 1H)7.70-7.80 (m, 1H) 7.67 (s, 1H) 7.40-7.50 (m, 1H) 7.19 (s, 1H, 6.99-7.12(m, 2H) 6.92 (s, 1H, 4.96 (s, 2H) 4.35-4.70 (m, 1H) 3.52 (br d, J=13.1Hz, 1H) 2.85-3.27 (m, 3H) 1.03-2.12 (m, 14H)

Compound (E5)

Major rotamer (65%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.36 (br s, 1H) 8.10 (br s, 1H)7.67-7.95 (m, 1H) 7.44 (br s, 1H) 6.70-7.17 (m, 2H) 5.83-6.25 (m, 1H)5.06-5.34 (m, 1H) 3.99 (br d, J=9.4 Hz, 1H) 3.45-3.81 (m, 1H) 3.09-3.25(m, 6H) 1.53-2.19 (m, 6H) 1.41 (br s, 3H) 1.22-1.34 (m, 2H) 1.13 (br s,3H)

Minor rotamer (35%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.36 (br s, 1H) 8.10 (br s, 1H)7.67-7.95 (m, 1H) 7.44 (br s, 1H) 6.70-7.17 (m, 2H) 5.83-6.25 (m, 1H)5.06-5.34 (m, 1H) 4.33-4.54 (m, 1H) 3.45-3.81 (m, 1H) 3.09-3.25 (m, 6H)1.53-2.19 (m, 6H) 1.41 (br s, 3H) 1.22-1.34 (m, 2H) 1.13 (br s, 3H)

Compound (E7)

Major rotamer (60%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.34 (s, 1H) 8.10 (t, J=8.5 Hz, 1H)7.81 (br d, J=13.4 Hz, 1H) 7.43 (br d, J=8.6 Hz, 1H) 7.03-7.10 (m, 2H)3.99 (br d, J=12.7 Hz, 1H) 3.49-3.76 (m, 3H) 2.73-3.26 (m, 6H) 2.59 (t,J=6.1 Hz, 2H) 1.88-2.13 (m, 1H) 1.53-1.85 (m, 4H) 1.41 (t, J=7 .5 Hz,3H) 1.22-1.36 (m, 3H) 1.10-1.20 (m, 3H)

Minor rotamer (40%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.34 (s, 1H) 8.10 (t, J=8.5 Hz, 1H)7.81 (br d, J=13.4 Hz, 1H) 7.43 (br d, J=8.6 Hz, 1H) 7.03-7.10 (m, 2H)4.39-4.49 (m, 1H) 3.49-3.76 (m, 3H) 2.73-3.26 (m, 6H) 2.59 (t, J=6.1 Hz,2H) 1.88-2.13 (m, 1H) 1.53-1.85 (m, 4H) 1.41 (t, J=7 .5 Hz, 3H)1.22-1.36 (m, 3H) 1.10-1.20 (m, 3H)

Compound (E10)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.58 (s, 1H) 8.10 (t, J=8.6 Hz, 1H)7.72-7.82 (m, 1H) 7.35-7.50 (m, 1H) 6.97-7.11 (m, 2H) 4.00 (br d, J=12.9Hz, 1H) 3.70-3.78 (m, 1H) 3.20-3.27 (m, 2H) 2.90 (t, J=12.2 Hz, 1H)1.06-2.16 (m, 15H) 0.76-0.91 (m, 4H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.58 (s, 1H) 8.10 (t, J=8.6 Hz, 1H)7.72-7.82 (m, 1H) 7.35-7.50 (m, 1H) 6.97-7.11 (m, 2H) 4.38-4.49 (m, 1H)3.55 (br d, J=12.9 Hz, 1H) 3.07-3.20 (m, 3H) 1.06-2.16 (m, 15H)0.76-0.91 (m, 4H)

Compound (E25)

Major rotamer (60%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.34 (br s, 1H) 8.09 (br t, J=7.9 Hz,1H) 7.79 (br d, J=13.6 Hz, 1H) 7.29-7.44 (m, 2H) 7.01-7.10 (m, 2H) 6.77(br s, 1H) 3.94-4.04 (m, 1H) 3.62-3.77 (m, 1H) 3.44-3.57 (m, 1H)3.05-3.27 (m, 3H) 2.85-3.00 (m, 1H) 2.53-2.61 (m, 1H) 1.49-2.12 (m, 5H)1.03-1.45 (m, 10H)

Minor rotamer (40%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.34 (br s, 1H) 8.09 (br t, J=7.9 Hz,1H) 7.79 (br d, J=13.6 Hz, 1H) 7.29-7.44 (m, 2H) 7.01-7.10 (m, 2H) 6.77(br s, 1H) 4.38-4.49 (m, 1H) 3.62-3.77 (m, 1H) 3.44-3.57 (m, 1H)3.05-3.27 (m, 3H) 2.85-3.00 (m, 1H) 2.53-2.61 (m, 1H) 1.49-2.12 (m, 5H)1.03-1.45 (m, 10H)

Compound (E27)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.34 (s, 1H, 8.05 (t, J=7.8 Hz, 1H)7.75-7.90 (m, 2H) 7.41 (d, J=7.9 Hz, 1H), 6.95-7.12 (m, 2H), 3.90-4.05(m, 1H), 3.62-3.75 (m, 1H) 3.25-3.30 (m, 2H) 2.91 (br d, J=12.9 Hz, 1H)2.35-2.70 (m, 6H) 1.06-2.15 (m, 15H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.34 (s, 1H, 8.05 (t, J=7.8 Hz, 1H)7.75-7.90 (m, 2H) 7.41 (d, J=7.9 Hz, 1H), 6.95-7.12 (m, 2H) 4.38-4.53(m, 1H) 3.52-3.61 (m, 1H) 3.25-3.30 (m, 2H) 3.05-3.20 (m, 1H) 2.35-2.70(m, 6H) 1.06-2.15 (m, 15H)

Compound (E28)

Major rotamer (60%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.34 (br s, 1H) 8.09 (t, J=8.7 Hz, 1H)7.79 (br d, J=13.2 Hz, 1H) 7.43 (br d, J=7.2 Hz, 1H) 7.01-7.09 (m, 2H)3.93-4.06 (m, 1H) 3.61-3.77 (m, 1H) 3.24 (q, J=7.0 Hz, 2H) 2.88-3.18 (m,4H) 2.82 (s, 3H) 2.56-2.66 (m, 4H) 1.86-2.13 (m, 1H) 1.51-1.85 (m, 4H)1.41 (br t, J=7.3 Hz, 3H) 1.21-1.36 (m, 3H) 1.07-1.19 (m, 3H)

Minor rotamer (40%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.34 (br s, 1H) 8.09 (t, J=8.7 Hz, 1H)7.79 (br d, J=13.2 Hz, 1H) 7.43 (br d, J=7.2 Hz, 1H) 7.05 (br t, J=7.2Hz, 2H) 4.38-4.50 (m, 1H) 3.54 (br d, J=14.9 Hz, 1H) 3.24 (q, J=7.0 Hz,2H) 2.88-3.18 (m, 4H) 2.82 (s, 3H) 2.56-2.66 (m, 4H) 1.86-2.13 (m, 1H)1.51-1.85 (m, 4H) 1.41 (br t, J=7.3 Hz, 3H) 1.21-1.36 (m, 3H) 1.07-1.19(m, 3H)

Compound (F15)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.5 (br s, 1H) 9.18-9.20 (m, 1H) 8.38(dd, J=8.2, 2.2 Hz, 1H) 8.34 (t, J=7.9 Hz, 1H) 8.17-8.28 (m, 3H) 7.21(d, J=3.8 Hz, 1H) 7.13 (br s, 1H) 4.00 (br d, J=13.2 Hz, 1H) 3.68-3.75(m, 1H) 3.22-3.31 (m, 2H) 2.94 (t, J=12.5 Hz, 1H) 1.91-1.98 (m, 1H)1.55-1.86 (m, 5H) 1.44 (t, J=7.4 Hz, 3H) 1.23-1.39 (m, 2H) 1.16 (d,J=6.6 Hz, 3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.5 (br s, 1H) 9.18-9.20 (m, 1H) 8.38(dd, J=8.2, 2.2 Hz, 1H) 8.34 (t, J=7.9 Hz, 1H) 8.17-8.28 (m, 3H) 7.23(d, J=3.8 Hz, 1H) 7.14 (br s, 1H) 4.41-4.49 (m, 1H) 3.55 (br d, J=13.2Hz, 1H) 3.22-3.31 (m, 2H) 3.11-3.18 (m, 1H) 2.03-2.10 (m, 1H) 1.55-1.86(m, 5H) 1.44 (t, J=7.4 Hz, 3H) 1.23-1.39 (m, 2H) 1.14 (d, J=6.6 Hz, 3H)

Compound (F16)

Major rotamer (60%)

¹H NMR (400 MHz, chloroform-d) δ ppm 8.05-8.16 (m, 1H) 7.78 (br s, 1H)7.37-7.53 (m, 2H) 7.32 (br d, J=5.6 Hz, 1H) 7.15 (t, J=4.3 Hz, 1H)6.58-6.96 (m, 2H) 4.26 (br d, J=13.2 Hz, 1H) 3.92-4.02 (m, 1H) 2.87-3.26(m, 3H) 1.93-2.21 (m, 1H) 1.64-1.75 (m, 1H) 1.21-1.49 (m, 12H)

Minor rotamer (40%)

¹H NMR (400 MHz, chloroform-d) δ ppm 8.05-8.16 (m, 1H) 7.78 (br s, 1H)7.37-7.53 (m, 2H) 7.32 (br d, J=5.6 Hz, 1H) 7.15 (t, J=4.3 Hz, 1H)6.58-6.96 (m, 2H) 4.61-4.74 (m, 1H) 3.85 (br d, J=15.3 Hz, 1H) 2.87-3.26(m, 3H) 1.93-2.21 (m, 1H) 1.64-1.75 (m, 1H) 1.21-1.49 (m, 12H)

Compound (F19):

Major rotamer (65%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.69 (br s, 1H) 9.01 (s, 1H) 8.38 (dd,J=11.7, 1.3 Hz, 1H) 8.32 (t, J=8.0 Hz, 1H) 8.03 (dd, J=12.3, 1.3 Hz, 1H)7.93 (dd, J=8.2, 1.6 Hz, 1H) 7.20-7.24 (m, 1H) 7.13 (s, 1H) 4.00 (br d,J=12.6 Hz, 1H) 3.65-3.77 (m, 1H) 3.28 (q, J=7.4 Hz, 2H) 2.94 (br t,J=12.6 Hz, 1H) 1.89-1.99 (m, 1H) 1.55-1.86 (m, 4H) 1.44 (t, J=7.6 Hz,3H) 1.20-1.40 (m, 3H) 1.10-1.19 (m, 3H)

Minor rotamer (35%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.69 (br s, 1H) 9.01 (s, 1H) 8.38 (dd,J=11.7, 1.3 Hz, 1H) 8.32 (t, J=8.0 Hz, 1H) 8.03 (dd, J=12.3, 1.3 Hz, 1H)7.93 (dd, J=8.2, 1.6 Hz, 1H) 7.20-7.24 (m, 1H) 7.14 (s, 1H) 4.39-4.49(m, 1H) 3.55 (br d, J=15.4 Hz, 1H) 3.28 (q, J=7.4 Hz, 2H) 3.10-3.18 (m,1H) 2.01-2.12 (m, 1H) 1.55-1.86 (m, 4H) 1.44 (t, J=7.6 Hz, 3H) 1.20-1.40(m, 3H) 1.10-1.19 (m, 3H)

Compound (F20):

Major rotamer (65%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.50 (br s, 1H) 8.23-8.38 (m, 1H)8.12-8.17 (m, 1H) 7.94-8.07 (m, 3H) 7.21-7.25 (m, 1H) 7.10-7.17 (m, 1H)3.97-4.04 (m, 1H) 3.67-3.76 (m, 1H) 3.28 (q, J=7.6 Hz, 2H) 2.94 (br t,J=12.5 Hz, 1H) 1.92-1.97 (m, 1H) 1.54-1.87 (m, 4H) 1.44 (t, J=7.4 Hz,3H) 1.22-1.38 (m, 3H) 1.12-118 (m, 3H)

Minor rotamer (35%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.50 (br s, 1H) 8.23-8.38 (m, 1H)8.12-8.17 (m, 1H) 7.94-8.07 (m, 3H) 7.21-7.25 (m, 1H) 7.10-7.17 (m, 1H)4.40-4.50 (m, 1H) 3.55 (br d, J=15.4 Hz, 1H) 3.28 (q, J=7.6 Hz, 2H)3.10-3.18 (m, 1H) 2.03-2.10 (m, 1H) 1.54-1.87 (m, 4H) 1.44 (t, J=7.4 Hz,3H) 1.22-1.38 (m, 3H) 1.12-118 (m, 3H)

Compound (F21):

Major rotamer (65%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.52 (br s, 1H) 9.19 (d, J=1.6 Hz, 1H)8.34-8.41 (m, 2H) 8.27 (d, J=8.2 Hz, 1H) 8.17-8.25 (m, 2H) 7.17-7.22 (m,1H) 6.85-6.89 (m, 1H) 3.98 (br d, J=13.2 Hz, 1H) 3.58-3.69 (m, 1H)2.85-3.05 (m, 2H) 1.87-1.99 (m, 1H) 1.19-1.87 (m, 11H) 1.07-1.19 (m, 3H)

Minor rotamer (35%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.52 (br s, 1H) 9.19 (d, J=1.6 Hz, 1H)8.34-8.41 (m, 2H) 8.27 (d, J=8.2 Hz, 1H) 8.17-8.25 (m, 2H) 7.17-7.22 (m,1H) 6.85-6.89 (m, 1H) 4.39-4.49 (m, 1H) 3.48 (br d, J=15.1 Hz, 1H)3.04-3.17 (m, 1H) 2.95-3.05 (m, 1H) 2.01-2.10 (m, 1H) 1.19-1.87 (m, 11H)1.07-1.19 (m, 3H)

Compound (F22):

Major rotamer (65%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.31 (br s, 1H) 9.17 (d, J=1.9 Hz, 1H)8.41 (dd, J=8.2, 2.2 Hz, 1H) 8.35 (t, J=7.9 Hz, 1H) 8.16 (d, J=8.2 Hz,1H) 7.98 (dd, J=12.5, 1.4 Hz, 1H) 7.88 (dd, J=8.2, 1.3 Hz, 1H) 7.34 (d,J=7.6 Hz, 1H) 7.06-7.29 (m, 5H) 5.63 (q, J=6.5 Hz, 1H) 3.92 (br dd,J=13.7, 3.9 Hz, 1H) 3.48-3.56 (m, 1H) 2.89-3.31 (m, 3H) 2.75 (br d,J=16.4 Hz, 1H) 1.55 (d, J=6.9 Hz, 3H) 1.40-1.48 (m, 3H)

Minor rotamer (35%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.31 (br s, 1H) 9.17 (d, J=1.9 Hz, 1H)8.41 (dd, J=8.2, 2.2 Hz, 1H) 8.35 (t, J=7.9 Hz, 1H) 8.16 (d, J=8.2 Hz,1H) 7.98 (dd, J=12.5, 1.4 Hz, 1H) 7.88 (dd, J=8.2, 1.3 Hz, 1H) 7.06-7.29(m, 6H) 5.06 (q, J=6.8 Hz, 1H) 4.59 (br dd, J=12.8, 3.3 Hz, 1H)2.84-3.31 (m, 5H) 1.59 (d, J=6.6 Hz, 3H) 1.40-1.48 (m, 3H)

Compound (F23):

Major rotamer (65%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.48 (br s, 1H) 9.19 (s, 1H) 7.96-8.54(m, 5H) 6.99-7.45 (m, 6H) 5.62 (q, J=6.6 Hz, 1H) 3.92 (br d, J=9.6 Hz,1H) 3.52 (br t, J=10.9 Hz, 1H) 2.89-3.32 (m, 3H) 2.75 (br d, J=16.2 Hz,1H) 1.55 (br d, J=6.6 Hz, 3H) 1.36-1.50 (m, 3H)

Minor rotamer (35%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.48 (br s, 1H) 9.19 (s, 1H) 7.96-8.54(m, 5H) 6.99-7.45 (m, 6H) 4.97-5.19 (m, 1H) 4.58 (br d, J=10.1 Hz, 1H)2.82-3.32 (m, 5H) 1.59 (br d, J=6.6 Hz, 3H) 1.36-1.50 (m, 3H)

Compound (F24):

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.32 (br s, 1H) 9.16 (d, J=1.9 Hz, 1H)8.41 (dd, J=8.2, 2.5 Hz, 1H) 8.33 (t, J=8.0 Hz, 1H) 8.15 (d, J=8.2 Hz,1H) 7.97 (dd, J=12.6, 1.6 Hz, 1H) 7.87 (dd, J=8.2, 1.6 Hz, 1H) 7.19-7.24(m, 1H) 7.11-7.15 (m, 1H) 4.00 (br d, J=13.6 Hz, 1H) 3.65-3.76 (m, 1H)3.25-3.31 (m, 2H) 2.94 (t, J=12.6 Hz, 1H) 1.89-2.00 (m, 1H) 1.54-1.86(m, 4H) 1.44 (t, J=7.6 Hz, 3H) 1.20-1.39 (m, 3H) 1.12-1.18 (m, 3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.32 (br s, 1H) 9.16 (d, J=1.9 Hz, 1H)8.41 (dd, J=8.2, 2.5 Hz, 1H) 8.33 (t, J=8.0 Hz, 1H) 8.15 (d, J=8.2 Hz,1H) 7.97 (dd, J=12.6, 1.6 Hz, 1H) 7.87 (dd, J=8.2, 1.6 Hz, 1H) 7.19-7.24(m, 1H) 7.11-7.15 (m, 1H) 4.40-4.50 (m, 1H) 3.55 (br d, J=15.1 Hz, 1H)3.25-3.31 (m, 2H) 3.10-3.18 (m, 1H) 2.02-2.12 (m, 1H) 1.54-1.86 (m, 4H)1.44 (t, J=7.6 Hz, 3H) 1.20-1.39 (m, 3H) 1.12-1.18 (m, 3H)

Compound (F25):

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.37 (br s, 1H) 8.82 (d, J=5.0 Hz, 1H)8.40 (d, J=1.3 Hz, 1H) 8.34 (t, J=8.0 Hz, 1H) 8.08 (dd, J=5.0, 1.9 Hz,1H) 8.01 (dd, J=12.3, 1.6 Hz, 1H) 7.92 (dd, J=8.2, 1.9 Hz, 1H) 7.20-7.25(m, 1H) 7.11-7.16 (m, 1H) 4.00 (br d, J=13.6 Hz, 1H) 3.66-3.76 (m, 1H)3.26-3.31 (m, 2H) 2.94 (t, J=12.5 Hz, 1H) 1.91-2.01 (m, 1H) 1.54-1.85(m, 4H) 1.44 (t, J=7.4 Hz, 3H) 1.21-1.39 (m, 3H) 1.12-1.18 (m, 3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.37 (br s, 1H) 8.82 (d, J=5.0 Hz, 1H)8.40 (d, J=1.3 Hz, 1H) 8.34 (t, J=8.0 Hz, 1H) 8.08 (dd, J=5.0, 1.9 Hz,1H) 8.01 (dd, J=12.3, 1.6 Hz, 1H) 7.92 (dd, J=8.2, 1.9 Hz, 1H) 7.20-7.25(m, 1H) 7.11-7.16 (m, 1H) 4.38-4.50 (m, 1H) 3.55 (br d, J=15.1 Hz, 1H)3.26-3.31 (m, 2H) 3.10-3.20 (m, 1H) 2.03-2.11 (m, 1H) 1.54-1.85 (m, 4H)1.44 (t, J=7.4 Hz, 3H) 1.21-1.39 (m, 3H) 1.12-1.18 (m, 3H)

Compound (F26)

Major rotamer: 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12-1.19 (m, 3H) 1.24-1.37 (m, 3H) 1.45(t, J=7.6 Hz, 3H) 1.59 (br s, 1H) 1.75-1.81 (m, 3H) 2.04-2.10 (m, 1H)2.94 (br t, J=12.4 Hz, 1H) 3.25-3.29 (m, 2H) 3.57 (br d, J=15.2 Hz, 1H)4.01 (br d, J=13.6 Hz, 1H) 7.14 (d, J=6.6 Hz, 1H) 7.36 (dd, J=7.1, 3.5Hz, 1H) 7.69 (dd, J=8.6, 4.0 Hz, 1H) 7.97 (d, J=8.6 Hz, 1H) 8.39 (dd,J=8.3, 6.8 Hz, 1H) 8.50 (d, J=8.1 Hz, 1H) 9.03 (dd, J=4.0, 1.5 Hz, 1H.

Minor rotamer: 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12-1.19 (m, 3H) 1.24-1.37 (m, 3H) 1.45(t, J=7.6 Hz, 3H) 1.59 (br s, 1H) 1.75-1.81 (m, 3H) 1.92-1.99 (m, 1H)3.11-3.18 (m, 1H) 3.25-3.29 (m, 2H) 3.71-3.76 (m, 1H) 4.46 (dt, J=11.9,6.2 Hz, 1H) 7.14 (d, J=6.6 Hz, 1H) 7.36 (dd, J=7.1, 3.5 Hz, 1H) 7.69(dd, J=8.6, 4.0 Hz, 1H) 7.97 (d, J=8.6 Hz, 1H) 8.39 (dd, J=8.3, 6.8 Hz,1H) 8.50 (d, J=8.1 Hz, 1H) 9.03 (dd, J=4.0, 1.5 Hz, 1H).

Compound (F27)

Major rotamer: 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12-1.19 (m, 3H) 1.24-1.37 (m, 3H) 1.45(t, J=7.6 Hz, 3H) 1.59 (br s, 1H) 1.75-1.81 (m, 3H) 2.04-2.10 (m, 1H)2.94 (br t, J=12.4 Hz, 1H) 3.25-3.29 (m, 2H) 3.57 (br d, J=15.2 Hz, 1H)4.01 (br d, J=13.6 Hz, 1H 7.14 (d, J=6.6 Hz, 1H) 7.36 (dd, J=7.1, 3.5Hz, 1H) 7.69 (dd, J=8.6, 4.0 Hz, 1H) 7.97 (d, J=8.6 Hz, 1H) 8.39 (dd,J=8.3, 6.8 Hz, 1H) 8.50 (d, J=8.1 Hz, 1H) 9.03 (dd, J=4.0, 1.5 Hz, 1H.

Minor rotamer: 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12-1.19 (m, 3H) 1.24-1.37 (m, 3H) 1.45(t, J=7.6 Hz, 3H) 1.59 (br s, 1H) 1.75-1.81 (m, 3H) 1.92-1.99 (m, 1H)3.11-3.18 (m, 1H) 3.25-3.29 (m, 2H) 3.71-3.76 (m, 1H) 4.46 (dt, J=11.9,6.2 Hz, 1H) 7.14 (d, J=6.6 Hz, 1H) 7.36 (dd, J=7.1, 3.5 Hz, 1H) 7.69(dd, J=8.6, 4.0 Hz, 1H) 7.97 (d, J=8.6 Hz, 1H) 8.39 (dd, J=8.3, 6.8 Hz,1H) 8.50 (d, J=8.1 Hz, 1H) 9.03 (dd, J=4.0, 1.5 Hz, 1H).

Compound (F28)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42-1.48 (m, 3H) 1.54-1.61 (m, 3H) 2.76(br d, J=16.2 Hz, 1H) 2.91-2.96 (m, 1H) 3.29 (s, 1H) 3.35-3.33 (m, 1H)3.89-3.98 (m, 1H) 5.07 (br d, J=6.6 Hz, 1H) 5.63 (q, J=6.4 Hz, 1H)7.08-7.27 (m, 4H) 7.34 (br d, J=7.1 Hz, 1H) 7.38-7.44 (m, 1H) 7.70 (dd,J=8.1, 4.0 Hz, 1H) 7.98 (br d, J=8.6 Hz, 1H) 8.41 (br t, J=7.6 Hz, 1H)8.51 (br d, J=8.1 Hz, 1H) 9.04 (br d, J=3.0 Hz, 1H.

Minor rotamer: 35%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42-1.48 (m, 3H) 1.54-1.61 (m, 3H) 2.76(br d, J=16.2 Hz, 1H) 3.02-3.11 (m, 1H) 3.29 (s, 1H) 3.35-3.33 (m, 1H)3.53 (br t, J=11.1 Hz, 1H) 4.54-4.63 (m, 1H) 7.08-7.27 (m, 4H) 7.34 (brd, J=7.1 Hz, 1H) 7.38-7.44 (m, 1H) 7.70 (dd, J=8.1, 4.0 Hz, 1H) 7.98 (brd, J=8.6 Hz, 1H) 8.41 (br t, J=7.6 Hz, 1H) 8.51 (br d, J=8.1 Hz, 1H)9.04 (br d, J=3.0 Hz, 1H)

Compound (F29)

Major rotamer (60%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12 (d, J=6.1 Hz, 3H) 1.20-1.46 (m, 6H)1.54-1.83 (m, 4H) 1.90-2.09 (m, 1H) 2.93 (br t, J=12.9 Hz, 1H) 3.20-3.28(m, 2H) 3.66-3.76 (m, 1H) 4.00 (br d, J=13.1 Hz, 1H) 5.06 (s, 2H)7.09-7.12 (m, 1H) 7.14 (d, J=6.4 Hz, 1H) 7.31 (d, J=8.1 Hz, 1H) 7.50 (s,1H) 7.70 (t, J=6.8 Hz, 1H) 12.95-13.18 (m, 1H)

Minor rotamer (40%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14 (d, J=6.1 Hz, 3H) 1.20-1.46 (m, 6H)1.54-1.83 (m, 4H) 1.90-2.09 (m,1H) 3.06-3.19 (m, 1H) 3.20-3.28 (m, 2H)3.54 (br d, J=14.1 Hz, 1H) 4.39-4.48 (m, 1H) 5.1 (s, 2H) 7.09-7.12 (m,1H) 7.14 (d, J=6.4 Hz, 1H) 7.31 (d, J=8.1 Hz, 1H) 7.50 (s, 1H) 7.70 (t,J=6.8 Hz, 1H) 12.95-13.18 (m, 1H)

Compound (F30)

Major rotamers (60%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12 (d, J=6.6 Hz, 3H) 1.21-1.36 (m, 3H)1.42 (t, J=7.3 Hz, 3H) 1.57-1.80 (m, 5H) 1.92-2.12 (m, 2H) 2.37-2.44 (m,2H) 2.93 (t, J=12.9 Hz,1H) 3.26 (q, J=7.3 Hz 3H) 3.70 (br s, 1H) 4.00(br d, J=13.6 Hz, 1H) 6.39 (br s, 1H) 7.07-7.12 (m, 2H) 7.38-7.46 (m,2H) 8.12 (t, J=8.3 Hz, 1H) 12.26 (br s, 1H)

Minor rotamers (40%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14 (d, J=6.6 Hz, 3H) 1.21-1.36 (m, 3H)1.42 (t, J=7.3 Hz, 3H) 1.57-1.80 (m, 5H) 1.92-2.12 (m, 2H) 2.37-2.44 (m,2H) 3.09-3.16 (m, 1H) 3.26 (q, J=7.3 Hz 3H) 3.54 (br s, 1H) 4.44 (m, 1H)6.39 (br s, 1H) 7.07-7.12 (m, 2H) 7.38-7.46 (m, 2H) 8.12 (t, J=8.3 Hz,1H) 12.26 (br s, 1H)

Compound (F31)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.14 (d, J=1.3 Hz, 1H) 8.26-8.37 (m, 2H)8.12-8.23 (m, 3H) 7.21 (d, J=3.8 Hz, 1H) 7.08 (s, 1H) 3.99 (br d, J=13.2Hz, 1H) 3.65-3.76 (m, 1H) 2.93 (br t, J=12.3 Hz, 1H) 1.89-1.99 (m, 1H)1.54-1.85 (m, 7H) 1.20-1.49 (m, 6H) 1.13 (d, J=6.3 Hz, 3H) 1.01 (br d,J=0.9 Hz, 2H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.14 (d, J=1.3 Hz, 1H) 8.26-8.37 (m, 2H)8.12-8.23 (m, 3H) 7.23 (d, J=3.8 Hz, 1H) 7.09 (s, 1H) 4.38-4.49 (m, 1H)3.52 (br d, J=15.4 Hz, 1H) 3.08-3.16 (m, 1H) 2.02-2.11 (m, 1H) 1.54-1.85(m, 7H) 1.20-1.49 (m, 6H) 1.15 (d, J=6.3 Hz, 3H) 1.01 (br d, J=0.9 Hz,2H)

Compound (F32)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.53 (br s, 1H) 9.19 (d, J=1.6 Hz, 1H)8.38 (dd, J=8.2, 2.2 Hz, 1H) 8.31-8.36 (m, 1H) 8.26 (d, J=8.2 Hz, 1H)8.15-8.23 (m, 2H) 7.20 (d, J=3.5 Hz, 1H) 7.14 (s, 1H) 4.31 (quin, J=8.6Hz, 1H) 4.01 (br d, J=13.2 Hz, 1H) 3.65-3.81 (m, 1H) 2.94 (br t, J=12.5Hz, 1H) 2.53-2.61 (m, 2H) 2.33-2.45 (m, 2H) 2.14-2.28 (m, 1H) 1.99-1.88(m, 2H) 1.87-1.52 (m, 4H) 1.21-1.49 (m, 3H) 1.14 (d, J=6.3 Hz, 3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.53 (br s, 1H) 9.19 (d, J=1.6 Hz, 1H)8.38 (dd, J=8.2, 2.2 Hz, 1H) 8.31-8.36 (m, 1H) 8.26 (d, J=8.2 Hz, 1H)8.15-8.23 (m, 2H) 7.21 (d, J=3.8 Hz, 1H) 7.15 (s, 1H) 4.40-4.49 (m, 1H)4.31 (quin, J=8.6 Hz, 1H) 3.55 (br d, J=15.4 Hz, 1H) 3.10-3.19 (m, 1H)2.53-2.61 (m, 2H) 2.33-2.45 (m, 2H) 2.13-2.02 (m, 1H) 1.99-1.88 (m, 2H)1.87-1.52 (m, 4H) 1.21-1.49 (m, 3H) 1.17 (d, J=6.3 Hz, 3H)

Compound (F33)

Major rotamer 70%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (d, J=6.6 Hz, 3H) 1.22-1.39 (m, 3H)1.47 (t, J=7.4 Hz, 4H) 1.59-1.89 (m, 4H) 1.93-1.99 (m 1H) 2.95 (t,J=12.9 Hz, 1H) 3.28-3.32 (m, 2H) 3.71-3.75 (m, 1H) 4.01 (br d, J=13.2Hz, 1H) 7.18 (d, J=7.6 Hz, 1H) 7.32 (dd, J=7.8, 3.8 Hz, 1H) 8.09-8.16(m, 2H) 8.78 (d, J=8.5 Hz, 1H) 8.90 (dd, J=8.2, 1.6 Hz, 1H) 13.61 (br s,1H)

Minor rotamer 30%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.6 Hz, 3H) 1.22-1.39 (m, 3H)1.47 (t, J=7.4 Hz, 4H) 1.59-1.89 (m, 4H) 2.04-2.10 (m1H) 3.13-3.18 (m,1H) 3.28-3.32 (m, 2H) 3.55-3.58 (m, 1H) 3.43-3.48 (m, 1H) 7.18 (d, J=7.6Hz, 1H) 7.32 (dd, J=7.8 Hz, J=3.8 Hz, 1H) 8.09-8.16 (m, 2H) 8.78 (d,J=8.5 Hz, 1H) 8.90 (dd, J=8.2, 1.6 Hz, 1H) 13.61 (br s, 1H

Compound (F34)

Major rotamer (60%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41-1.50 (m, 3H) 1.52-1.62 (m, 3H)2.74-3.11 (m, 2H) 3.24-3.37 (m, 2H) 3.42-3.57 (m, 1H) 3.93 (br dd,J=13.6, 4.6 Hz, 1H) 5.60-5.66 (m, 1H) 7.07-7.26 (m, 4H) 7.32-7.42 (m,2H) 8.14 (dd, J=8.6, 3.5 Hz, 2H) 8.29 (d, J=8.6 Hz, 1H) 8.38 (t, J=8.1Hz, 1H) 8.71 (s, 1H) 13.18-13.43 (m, 1H)

Minor rotamer (40%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41-1.50 (m, 3H) 1.52-1.62 (m, 3H)2.74-3.11 (m, 2H) 3.24-3.37 (m, 2H) 3.42-3.57 (m, 1H) 4.56-4.62 (m, 1H)5.06 (br d, J=6.6 Hz, 1H) 7.07-7.26 (m, 4H) 7.32-7.42 (m, 2H) 8.14 (dd,J=8.6, 3.5 Hz, 2H) 8.29 (d, J=8.6 Hz, 1H) 8.38 (t, J=8.1 Hz, 1H) 8.71(s, 1H) 13.18-13.43 (m, 1H)

Compound (F35)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35-1.41 (m, 1H) 1.43 (t, J=7.58 Hz,3H) 1.45-1.81 (m, 5H) 1.80-1.89 (m, 1H) 2.45 (s, 3H) 3.03-3.11 (m, 1H)3.15-3.23 (m, 1H)3.22-3.29 (q, J=7.58, 14.65 Hz, 2H) 3.93 (d, J=13.64Hz, 1H) 7.06 (s, 1H) 7.15 (d, J=3.54 Hz, 1H) 8.16-8.40 (m, 5H) 9.19 (d,J=2.02 Hz, 1H) 13.48 (m, 1H)

Compound (F36)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (dd, J=8.5, 6.6 Hz, 3H) 1.22-1.40(m, 3H) 1.46 (t, J=7.4 Hz, 3H) 1.60-1.85 (m, 4H) 1.92-2.02 (m, 1H) 2.95(br t, J=12.5 Hz, 1H) 3.25-3.30 (m, 2H) 3.70-3.78 (m, 1H) 4.02 (br d,J=13.2 Hz, 1H) 7.14 (d, J=8.2 Hz, 1H) 7.34 (dd, J=8.4, 3.3 Hz, 1H) 8.03(d, J=8.8 Hz, 1H) 8.11-8.19 (m, 2H) 8.44 (t, J=7.9 Hz, 1H) 8.80 (s, 1H)13.27-13.48 (m, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (dd, J=8.5, 6.6 Hz, 3H) 1.22-1.40(m, 3H) 1.46 (t, J=7.4 Hz, 3H) 1.60-1.85 (m, 4H) 1.92-2.02 (m, 1H)3.10-3.22 (m, 1H) 3.25-3.30 (m, 2H) 3.57 (br d, J=15.8 Hz, 1H) 4.47 (dt,J=12.0, 6.0 Hz, 1H) 7.14 (d, J=8.20 Hz, 1H) 7.34 (dd, J=8.4, 3.3 Hz, 1H)8.03 (d, J=8.8 Hz, 1H) 8.11-8.19 (m, 2H) 8.44 (t, J=7.9 Hz, 1H) 8.80 (s,1H) 13.27-13.48 (m, 1H)

Compound (F37)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.12 (d, J=6.3 Hz, 3H), 1.25-1.29 (m,3H), 1.40-1.43 (t, J=7.6 Hz, 3H), 1.46-1.62 (m, 5H), 1.67-1.80 (m, 3H),1.88-2.09 (m, 5H), 2.19-2.23 (t, J=10.7 Hz, 1H, 2.56-2.61 (m, 1H,3.10-3.15 (m, 1H, 3.21-3.27 (q, J=7.6, 14.8 Hz, 2H), 3.67-3.74 (m, 1H,3.99 (d, J=13.2 Hz, 1H, 7.06-7.09 (m, 2H) 7.25 (dd, J=7.4, 6.5 Hz, 2H)8.06 (t, J=7.9 Hz, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (d, J=6.3 Hz, 3H), 1.25-1.29 (m,3H), 1.40-1.43 (t, J=7.6 Hz, 3H), 1.46-1.62 (m, 5H), 1.67-1.80 (m, 3H),1.88-2.09 (m, 5H), 2.19-2.23 (t, J=10.7 Hz, 1H, 2.56-2.61 (m, 1H,2.90-2.95 (t, J=12 Hz, 1H, 3.21-3.27 (q, J=7.6, 14.8 Hz, 2H), 3.52-3.35(m, 1H, 4.40-4.47 (m, 1H, 7.06-7.09 (m, 2H) 7.25 (dd, J=7.4, 6.5 Hz,2H), 8.06 (t, J=7.9 Hz, 1H)

Compound (F38)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.10 (d, J=6.3 Hz, 3H), 1.23-1.36 (m,6H), 1.39-1.80 (m, 5H), 1.90-1.95 (m, 1H, 2.88-2.96 (m, 2H), 3.62-3.66(m, 1H, 3.99 (d, J=13.2 Hz, 1H, 5.07 (d, J=1.6 Hz, 2H) 6.85 (d, J=1.6Hz, 1H) 7.12 (dd, J=8.8, 3.5 Hz, 1H) 7.31 (d, J=8.2 Hz, 1H) 7.50 (s, 1H)7.71 (t, J=7.2 Hz, 1H, 13.2 (bs, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (d, J=6.3 Hz, 3H), 1.23-1.36 (m,6H), 1.39-1.80 (m, 5H), 2.02-2.07 (m, 1H, 2.88-2.96 (m, 1H, 3.06-3.12(m, 1H, 3.45-3.48 (d, J=15.5 Hz, 1H, 4.39-4.44 (m, 1H, 5.07 (d, J=1.6Hz, 2H) 6.85 (d, J=1.6 Hz, 1H) 7.12 (dd, J=8.8, 3.5 Hz, 1H) 7.31 (d,J=8.2 Hz, 1H) 7.50 (s, 1H) 7.71 (t, J=7.2 Hz, 1H, 13.2 (bs, 1H)

Compound (F39)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (d, J=6.3 Hz, 3H) 1.20-1.38 (m, 3H)1.39-1.48 (m, 1H) 1.56-1.66 (m, 2H) 1.68-1.83 (m, 2H) 1.89-2.09 (m, 2H)2.13-2.24 (m, 1H) 2.32-2.48 (m, 2H) 2.52-2.57 (m, 1H) 2.94 (t, J=12.5Hz, 1H) 3.72 (dt, J=10.1, 6.3 Hz, 1H) 4.00 (br d, J=13.6 Hz, 1H)4.23-4.27 (m, 1H) 5.07 (d, J=1.3 Hz, 2H) 7.11-7.15 (m, 2H) 7.32 (d,J=7.9 Hz, 1H) 7.53 (s, 1H) 7.70 (t, J=7.1 Hz, 1H) 12.94-13.17 (br s, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (dd, J=6.3 Hz, 3H) 1.20-1.38 (m,3H) 1.39-1.48 (m, 1H) 1.56-1.66 (m, 2H) 1.68-1.83 (m, 2H) 1.89-2.09 (m,2H) 2.13-2.24 (m, 1H) 2.32-2.48 (m, 2H) 2.52-2.57 (m, 1H) 3.09-3.21 (m,1H) 3.54 (br d, J=15.1 Hz, 1 H) 4.23-4.27 (m, 1H) 4.45 (dt, J=12.1, 6.11Hz, 1H) 5.07 (d, J=1.3 Hz, 2H) 7.11-7.15 (m, 2H) 7.32 (d, J=7.88 Hz, 1H)7.53 (s, 1H) 7.70 (t, J=7.1 Hz, 1H) 12.94-13.17 (br s, 1 H)

Compoud (F40)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (d, J=6.3 Hz, 3H) 1.22-1.39 (m, 3H)1.44 (t, J=7.6 Hz, 3H) 1.56-1.84 (m, 4H) 1.92-1.98 (m, 1H) 2.94 (t,J=12.5, 1H) 3.25-3.29 (m, 2H) 3.68-3.75 (m, 1H) 4.01 (br d, J=13.6 Hz,1H) 7.12 (d, J=8.2 Hz, 1H) 7.23 (dd, J=7.6, 3.5 Hz, 1H) 7.92 (d, J=8.2Hz, 1H) 8.17 (t, J=7.1 Hz, 1H) 8.86 (s, 1H) 13.32 (br s, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.3 Hz, 3H) 1.22-1.39 (m, 3H)1.44 (t, J=7.6 Hz, 3H) 1.56-1.84 (m, 4H) 2.04-2.08 (m, 1H) 3.11-3.18 (m,1H) 3.25-3.29 (m, 2H) 3.55 (br d, J=15.5 Hz, 1H) 4.45 (dt, J=12.1, 6.1Hz, 1H) 7.12 (d, J=8.2 Hz, 1H) 7.23 (dd, J=7.6, 3.5 Hz, 1H) 7.92 (d,J=8.2 Hz, 1H) 8.17 (t, J=7.1 Hz, 1H) 8.86 (s, 1H) 13.32 (br s, 1H)

Compound (I1)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.25 (t, J=7.6 Hz, 1H) 8.17 (s, 1H)7.80-7.90 (m, 2H) 7.58 (s, 1H) 7.08-7.22 (m, 2H) 3.99 (br d, J=13.2 Hz,1H) 3.65-3.75 (m, 1H) 3.18-3.30 (m, 2H) 2.93 (t, J=12.2 Hz, 1H)1.05-2.15 (m, 14H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.25 (t, J=7.6 Hz, 1H) 8.17 (s, 1H)7.80-7.90 (m, 2H) 7.58 (s, 1H) 7.08-7.22 (m, 2H) 4.38-4.50 (m, 1H) 3.50(br d, J=13.2 Hz, 1H) 3.05-3.30 (m, 3H) 1.15-2.15 (m, 14H)

Compound (I2)

Major rotamer (60%)

¹H NMR (400 MHz, chloroform-d) δ ppm 8.24-8.35 (m, 1H) 7.53-7.73 (m, 2H)7.22 (dd, J=5.1, 4.0 Hz, 1H) 6.90 (s, 1H) 6.54 (br s, 1H) 5.74 (br s,1H) 4.25 (br d, J=14.8 Hz, 1H) 3.96-4.04 (m, 1H) 3.22-3.35 (m, 2H)2.84-3.18 (m, 1H) 1.64-2.24 (m, 6H) 1.19-1.56 (m, 8H)

Minor rotamer (40%)

¹H NMR (400 MHz, chloroform-d) δ ppm 8.24-8.35 (m, 1H) 7.53-7.73 (m, 2H)7.22 (dd, J=5.1, 4.0 Hz, 1H) 6.95 (s, 1H) 6.54 (br s, 1H) 5.74 (br s,1H) 4.59-4.75 (m, 1H) 3.87 (br d, J=15.3 Hz, 1H) 3.22-3.35 (m, 2H)2.84-3.18 (m, 1H) 1.64-2.24 (m, 6H) 1.19-1.56 (m, 8H)

Compound (I12)

Major rotamer (65%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.27 (br t, J=7.9 Hz, 1H) 8.15 (br s,1H) 7.79-7.93 (m, 2H) 7.59 (br s, 1H) 7.02-7.37 (m, 6H) 5.62 (br d,J=7.2 Hz, 1H) 3.91 (br d, J=10.4 Hz, 1H) 3.51 (br t, J=10.8 Hz, 1H)2.68-3.28 (m, 4H) 1.54 (br d, J=6.7 Hz, 3H) 1.37-1.47 (m, 3H)

Minor rotamer (35%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.27 (br t, J=7.9 Hz, 1H) 8.15 (br s,1H) 7.79-7.93 (m, 2H) 7.59 (br s, 1H) 7.02-7.37 (m, 6H) 5.04 (br d,J=6.6 Hz, 1H) 4.57 (br s, 1H) 2.68-3.28 (m, 5H) 1.58 (br d, J=6.7 Hz,3H) 1.37-1.47 (m, 3H)

Compound (I31)

Major rotamer (65%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.14-8.24 (m, 2H) 7.82-7.93 (m, 3H) 7.65(s, 1H) 7.41-7.50 (m, 1H) 3.75-4.10 (m, 2H) 2.95 (t, J=12.1 Hz, 1H)1.11-2.11 (m, 11H)

Minor rotamer (35%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.14-8.24 (m, 2H) 7.82-7.93 (m, 3H) 7.65(s, 1H) 7.41-7.50 (m, 1H) 4.35-4.47 (m, 1H) 3.62 (br d, J=13.2 Hz, 1H)3.10-3.20 (m, 1H) 1.11-2.11 (m, 11H)

Compound (133)

Major rotamer (65%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.25 (t, J=7.6 Hz, 1H) 8.13 (s, 1H)7.80-7.90 (m, 2H) 7.58 (s, 1H) 7.14-7.23 (m, 1H) 6.91 (s, 1H) 3.00-4.00(m, 9H) 1.06-2.05 (m, 12H)

Minor rotamer (35%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.25 (t, J=7.6 Hz, 1H) 8.13 (s, 1H)7.80-7.90 (m, 2H) 7.58 (s, 1H) 7.14-7.23 (m, 1H) 7.05 (s, 1H) 4.35-4.48(m, 1H) 3.23-4.57 (m, 8H) 1.06-2.05 (m, 12H)

Compound (J1)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.19 (s, 1H, 7.85-7.98 (m, 3H) 7.64 (s,1H) 7.15-7.20 (m, 1H) 4.03 (br d, J=13.2 Hz, 1H) 3.70-3.90 (m, 1H)3.18-3.25 (m, 2H) 2.95 (t, J=12.4 Hz, 1H) 1.15-2.15 (m, 14H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.19 (s, 1H, 7.85-7.98 (m, 3H) 7.64 (s,1H) 7.15-7.20 (m, 1H) 4.38-4.50 (m, 1H) 3.55 (br d, J=13.1 Hz, 1H)3.10-3.25 (m, 3H) 1.15-2.15 (m, 14H)

Compound (L1)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.63 (br s, 1H) 8.25 (t, J=7.9 Hz, 1H)7.75-7.90 (m, 2H) 7.05-7.25 (m, 2H) 4.00 (br d, J=12.9 Hz, 1H) 3.65-3.75(m, 1H) 2.70-3.40 (m, 4H) 1.07-2.09 (m, 14H) 0.52-0.80 (m, 4H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.63 (br s, 1H) 8.25 (t, J=7.9 Hz, 1H)7.75-7.90 (m, 2H) 7.05-7.25 (m, 2H) 4.38-4.55 (m, 1H) 3.52 (br d, J=12.9Hz, 1H) 2.70-3.40 (m, 4H) 1.07-2.09 (m, 14H) 0.52-0.80 (m, 4H)

Compound (L6)

Major rotamer (60%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.40 (br s, 1H) 8.25 (t, J=7.7 Hz, 1H)7.71-7.79 (m, 2H) 7.11-7.21 (m, 3H) 4.00 (br d, J=14.3 Hz, 1H) 3.52-3.78(m, 2H) 2.92-3.31 (m, 3H) 1.90-2.08 (m, 1H) 1.53-1.82 (m, 4H) 1.43 (brt, J=7.6 Hz, 3H) 1.30 (br d, J=7.0 Hz, 2H) 1.14 (br dd, J=10.6, 6.5 Hz,3H)

Minor rotamer (40%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.40 (br s, 1H) 8.25 (t, J=7.7 Hz, 1H)7.71-7.79 (m, 2H) 7.11-7.21 (m, 3H) 4.42-4.52 (m, 1H) 3.52-3.78 (m, 2H)2.92-3.31 (m, 3H) 1.90-2.08 (m, 1H) 1.53-1.82 (m, 4H) 1.43 (br t, J=7.6Hz, 3H) 1.30 (br d, J=7.0 Hz, 2H) 1.14 (br dd, J=10.6, 6.5 Hz, 3H)

Compound (M6)

Major rotamer (65%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.48 (br s, 1H) 7.80-8.08 (m, 3H)7.69-7.73 (m, 1H) 7.62 (d, J=16.0 Hz, 1H) 7.30 (s, 1H) 7.02-7.27 (m, 5H)6.70 (d, J=16.0 Hz, 1H) 5.60 (q, J=6.5 Hz, 1H) 3.86-3.98 (m, 1H)2.70-3.55 (m, 4H) 1.29-1.62 (m, 6H)

Minor rotamer (35%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.48 (br s, 1H) 7.80-8.08 (m, 3H)7.69-7.73 (m, 1H) 7.62 (d, J=16.0 Hz, 1H) 7.30 (s, 1H) 7.02-7.27 (m, 5H)6.70 (d, J=16.0 Hz, 1H) 5.04 (q, J=6.5 Hz, 1H) 4.50-4.65 (m, 1H)2.70-3.55 (m, 4H) 1.29-1.62 (m, 6H)

Compound (M7)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.63 (br s, 1H) 8.21 (br t, J=7.7 Hz,1H) 7.81 (br d, J=12.3 Hz, 1H) 7.71 (br d, J=7.9 Hz, 1H) 7.64 (br d,J=15.8 Hz, 1H) 7.07-7.24 (m, 2H) 6.71 (br d, J=16.1 Hz, 1H) 4.00 (br d,J=12.9 Hz, 1H) 3.64-3.76 (m, 1H) 3.17-3.30 (m, 2H) 2.94 (br t, J=12.6Hz, 1H) 1.88-2.01 (m, 1H) 1.05-1.86 (m, 13H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.63 (br s, 1H) 8.21 (br t, J=7.7 Hz,1H) 7.81 (br d, J=12.3 Hz, 1H) 7.71 (br d, J=7.9 Hz, 1H) 7.64 (br d,J=15.8 Hz, 1H) 7.07-7.24 (m, 2H) 6.71 (br d, J=16.1 Hz, 1H) 4.37-4.53(m, 1H) 3.54 (br d, J=14.8 Hz, 1H) 3.07-3.30 (m, 3H) 2.02-2.11 (m, 1H)1.05-1.86 (m, 13H)

Compound (M8)

Major rotamer (70%)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.26 (t, J=7.9 Hz, 1H) 7.93 (br s, 1H)7.51-7.79 (m, 3H) 7.00-7.38 (m, 4H) 6.86 (d, J=3.5 Hz, 1H) 6.63 (d,J=15.9 Hz, 1H) 6.26 (br s, 1H) 5.62 (br s, 1H) 3.94 (s, 1H) 3.23-3.57(m, 2H) 3.08 (br s, 3H) 2.71-2.94 (m, 2H) 1.56 (br d, J=6.3 Hz, 3H)

Minor rotamer (30%)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.26 (t, J=7.9 Hz, 1H) 7.93 (br s, 1H)7.51-7.79 (m, 3H) 7.00-7.38 (m, 4H) 6.86 (d, J=3.5 Hz, 1H) 6.63 (d,J=15.9 Hz, 1H) 6.26 (br s, 1H) 5.09 (s, 1H) 4.55 (s, 1H) 3.23-3.57 (m,2H) 3.08 (br s, 3H) 2.71-2.94 (m, 2H) 1.56 (br d, J=6.3 Hz, 3H)

Compound (M10)

Major rotamer (65%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.55 (br s, 1H) 8.15 (t, J=7.9 Hz, 1H)7.60-7.82 (m, 3H) 7.02-7.43 (m, 4H) 6.92 (br s, 1H) 6.62 (d, J=15.9 Hz,1H) 6.35 (s, 1H) 5.60 (q, J=6.6 Hz, 1H) 3.80-3.90 (m, 1H) 3.48 (s, 6H)2.60-3.41 (m, 3H) 1.50 (d, J=6.4 Hz, 3H)

Minor rotamer (35%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.55 (br s, 1H) 8.15 (t, J=7.9 Hz, 1H)7.60-7.82 (m, 3H) 7.02-7.43 (m, 4H) 6.92 (br s, 1H) 6.62 (d, J=15.9 Hz,1H) 6.30 (s, 1H) 5.05 (q, J=6.6 Hz, 1H) 4.50-4.55 (m, 1H) 3.45 (s, 6H)2.60-3.41 (m, 3H) 1.55 (d, J=6.4 Hz, 3H)

Compound (M14):

Major rotamer (65%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.56 (br s, 1H) 8.26-8.31 (m, 2H) 7.80(br d, J=12.0 Hz, 1H) 7.73 (br d, J=8.2 Hz, 1H) 7.64 (d, J=15.8 Hz, 1H)7.33 (d, J=7.6 Hz, 1H) 7.05-7.29 (m, 2H) 6.85-6.94 (m, 1H) 6.71 (d,J=16.1 Hz, 1H) 6.31 (s, 1H) 5.60 (q, J=6.9 Hz, 1H) 3.84 (br dd, J=13.2,4.4 Hz, 1H) 3.42-3.53 (m, 1H) 3.19-3.32 (m, 1H) 2.82-3.08 (m, 4H) 2.72(br d, J=16.7 Hz, 1H) 1.52 (d, J=6.6 Hz, 3H)

Minor rotamer (35%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.56 (br s, 1H) 8.26-8.31 (m, 2H) 7.80(br d, J=12.0 Hz, 1H) 7.73 (br d, J=8.2 Hz, 1H) 7.64 (d, J=15.8 Hz, 1H)7.05-7.29 (m, 3H) 6.85-6.94 (m, 1H) 6.71 (d, J=16.1 Hz, 1H) 6.27 (s, 1H)4.96-5.04 (m, 1H) 4.58 (br d, J=12.6 Hz, 1H) 3.42-3.53 (m, 1H) 3.19-3.32(m, 1H) 2.82-3.08 (m, 5H) 1.57 (d, J=6.6 Hz, 3H)

Compound (M15):

Major rotamer (65%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.59 (br s, 1H) 8.22 (t, J=8.0 Hz, 1H)7.82 (br d, J=12.3 Hz, 1H) 7.71 (br d, J=8.2 Hz, 1H) 7.64 (d, J=15.8 Hz,1H) 7.34 (br d, J=7.6 Hz, 1H) 7.10-7.27 (m, 5H) 6.71 (d, J=16.1 Hz, 1H)5.62 (q, J=6.6 Hz, 1H) 3.91 (br dd, J=13.6, 3.5 Hz, 1H) 3.46-3.54 (m,1H) 3.22-3.30 (m, 2H) 2.91-3.10 (m, 1H) 2.86-2.90 2.75 (br d, J=16.1 Hz,1H) 1.54 (d, J=6.6 Hz, 3H) 1.38-1.48 (m, 3H)

Minor rotamer (35%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.59 (br s, 1H) 8.22 (t, J=8.0 Hz, 1H)7.82 (br d, J=12.3 Hz, 1H) 7.71 (br d, J=8.2 Hz, 1H) 7.64 (d, J=15.8 Hz,1H) 7.10-7.27 (m, 5H) 7.06-7.10 (m, 1H) 6.71 (d, J=16.1 Hz, 1H) 5.04 (q,J=6.4 Hz, 1H) 4.54-4.62 (m, 1H) 3.46-3.54 (m, 1H) 3.22-3.30 (m, 2H)2.91-3.10 (m, 2H) 1.58 (d, J=6.6 Hz, 3H) 1.38-1.48 (m, 3H)

Compound (M16):

Major rotamer (65%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.58 (br s, 1H) 8.16 (br t, J=7.9 Hz,1H) 7.79 (br d, J=12.3 Hz, 1H) 7.61-7.74 (m, 2H) 7.32 (br d, J=7.6 Hz,1H) 7.01-7.27 (m, 3H) 6.80-6.90 (m, 1H) 6.69 (d, J=15.8 Hz, 1H) 6.11 (s,1H) 5.58 (q, J=6.5 Hz, 1H) 4.28 (br t, J=6.1 Hz, 1H) 3.85 (br dd,J=13.6, 3.8 Hz, 1H) 3.43-3.51 (m, 2H) 3.20-3.27 (m, 2H) 2.81-3.09 (m,1H) 2.72 (br d, J=16.1 Hz, 1H) 1.95-2.06 (m, 4H) 1.51 (br d, J=6.9 Hz,3H)

Minor rotamer (35%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.58 (br s, 1H) 8.16 (br t, J=7.9 Hz,1H) 7.79 (br d, J=12.3 Hz, 1H) 7.61-7.74 (m, 2H) 7.01-7.27 (m, 4H)6.80-6.90 (m, 1H) 6.69 (d, J=15.8 Hz, 1H) 6.07 (s, 1H) 5.02 (q, J=6.5Hz, 1H) 4.52-4.60 (m, 1H) 4.28 (br t, J=6.1 Hz, 1H) 3.43-3.51 (m, 2H)3.20-3.27 (m, 2H) 2.81-3.09 (m, 2H) 1.95-2.06 (m, 4H) 1.56 (br d, J=6.6Hz, 3H)

Compound (M17):

Major rotamer (65%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.71 (br s, 1H) 8.24 (t, J=8.0 Hz, 1H)7.62 (s, 1H) 7.47-7.58 (m, 2H) 7.34 (d, J=7.3 Hz, 1H) 7.11-7.27 (m, 5H)5.62 (q, J=6.6 Hz, 1H) 3.91 (br dd, J=13.7, 3.6 Hz, 1H) 3.48-3.55 (m,1H) 3.27 (q, J=7.7 Hz, 2H) 2.91-3.11 (m, 1H) 2.75 (br d, J=16.7 Hz, 1H)2.10 (d, J=0.9 Hz, 3H) 1.54 (d, J=6.6 Hz, 3H) 1.39-1.47 (m, 3H)

Minor rotamer (35%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.71 (br s, 1H) 8.24 (t, J=8.0 Hz, 1H)7.62 (s, 1H) 7.47-7.58 (m, 2H) 7.11-7.27 (m, 5H) 7.06-7.10 (m, 1H) 5.05(q, J=6.7 Hz, 1H) 4.58 (br dd, J=13.4, 3.9 Hz, 1H) 3.21-3.31 (m, 3H)2.91-3.11 (m, 1H) 2.84-2.91 (m, 1H) 2.10 (d, J=0.9 Hz, 3H) 1.59 (d,J=6.6 Hz, 3H) 1.39-1.47 (m, 3H)

Compound (M18):

Major rotamer (70%):

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40 (t, J=7.1 Hz, 3H) 1.65 (br d, J=7.1Hz, 3H) 1.73-2.05 (m, 2H) 2.78-2.98 (m, 1H) 3.08-3.18 (m, 1H) 3.24 (q,J=7.1 Hz, 2H) 3.36-3.47 (m, 1H) 3.49-3.65 (m, 1H) 3.65-3.77 (m, 1H)5.62-5.87 (m, 1H) 6.66-6.78 (m, 2H) 7.07-7.23 (m, 3H) 7.34 (br d, J=4.04Hz, 1H) 7.63 (d, J=16.2 Hz, 1H) 7.67-7.74 (m, 1H) 7.80 (d, J=11.6 Hz,1H) 8.20 (t, J=8.1 Hz, 1H) 12.58 (br s, 1H

Minor rotamer (30%):

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, J=7.1 Hz, 3H) 1.57 (d, J=7.1Hz, 3H)) 1.73-2.05 (m, 2H) 2.78-2.98 (m, 1H) 3.08-3.18 (m, 1H) 3.24 (q,J=7.1 Hz, 2H) 3.36-3.47 (m, 1H) 4.57 (br d, J=13.6 Hz, 1H) 5.08 (d,J=7.1 Hz, 1H) 7.04 (t, J=7.1 Hz, 1H) 7.07-7.23 (m, 6H) 7.64 (d, J=16.2Hz, 1H) 7.67-7.74 (m, 1H) 7.82 (d, J=11.6 Hz, 1H) 8.23 (t, J=8.1 Hz, 1H)12.58 (br s, 1H)

Compound (M19):

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.58 (br s, 1H) 8.20 (t, J=8.0 Hz, 1H)7.81 (d, J=12.0 Hz, 1H) 7.67-7.72 (m, 1H) 7.63 (d, J=15.8 Hz, 1H)7.10-7.19 (m, 2H) 6.70 (d, J=16.1 Hz, 1H) 4.23-4.36 (m, 1H) 4.00 (br d,J=13.2 Hz, 1H) 3.66-3.77 (m, 1H) 2.94 (t, J=12.5 Hz, 1H) 2.53-2.61 (m,2H) 2.34-2.44 (m, 2H) 2.14-2.25 (m, 1H) 1.88-2.11 (m, 2H) 1.52-1.86 (m,4H) 1.20-1.50 (m, 3H) 1.13 (d, J=6.3 Hz, 3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.58 (br s, 1H) 8.20 (t, J=8.0 Hz, 1H)7.81 (d, J=12.0 Hz, 1H) 7.67-7.72 (m, 1H) 7.63 (d, J=15.8 Hz, 1H)7.10-7.19 (m, 2H) 6.70 (d, J=16.1 Hz, 1H) 4.45 (dt, J=11.9, 6.2 Hz, 1H)3.66-3.77 (m, 1H) 3.54 (br d, J=15.8 Hz, 1H) 3.13 (br dd, J=14.7, 9.9Hz, 1H) 2.53-2.61 (m, 2H) 2.34-2.44 (m, 2H) 2.14-2.25 (m, 1H) 1.88-2.11(m, 2H) 1.52-1.86 (m, 4H) 1.20-1.50 (m, 3H) 1.16 (d, J=6.3 Hz, 3H)

Compound (M20)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.61 (br s, 1H) 8.22 (br t, J=7.9 Hz,1H) 7.82 (br d, J=12.3 Hz, 1H) 7.72 (br d, J=7.9 Hz, 1H) 7.64 (br d,J=15.8 Hz, 1H) 7.15-7.22 (m, 1H) 7.05-7.12 (m, 1H) 6.70 (br d, J=15.8Hz, 1H) 3.98 (br d, J=12.9 Hz, 1H) 3.64-3.74 (m, 1H) 2.93 (br t, J=12.5Hz, 1H) 1.88-1.98 (m, 1H) 1.50-1.84 (m, 7H) 1.07-1.49 (m, 8H) 0.99 (brs, 2H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.61 (br s, 1H) 8.22 (br t, J=7.9 Hz,1H) 7.82 (br d, J=12.3 Hz, 1H) 7.72 (br d, J=7.9 Hz, 1H) 7.64 (br d,J=15.8 Hz, 1H) 7.18 (br dd, J=7.3, 3.2 Hz, 1H) 7.08 (d, J=6.9 Hz, 1H)6.70 (br d, J=15.8 Hz, 1H) 4.37-4.48 (m, 1H) 3.50 (br d, J=15.4 Hz, 1H)3.07-3.15 (m, 1H) 2.01-2.08 (m, 1H) 1.50-1.84 (m, 7H) 1.07-1.49 (m, 8H)0.99 (br s, 2H)

Compound (M21):

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.56 (br s, 1H) 8.22 (br t, J=7.7 Hz,1H) 7.81 (br d, J=12.3 Hz, 1H) 7.70 (br d, J=8.2 Hz, 1H) 7.63 (br d,J=15.8 Hz, 1H) 7.10-7.21 (m, 1H) 6.86 (s, 1H) 6.70 (br d, J=16.1 Hz, 1H)3.97 (br d, J=12.9 Hz, 1H) 3.55-3.65 (m, 1H) 2.85-3.14 (m, 2H) 1.86-1.97(m, 1H) 1.20-1.87 (m, 11H) 1.10 (br d, J=6.0 Hz, 3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.56 (br s, 1H) 8.22 (br t, J=7.7 Hz,1H) 7.81 (br d, J=12.3 Hz, 1H) 7.70 (br d, J=8.2 Hz, 1H) 7.63 (br d,J=15.8 Hz, 1H) 7.10-7.21 (m, 1H) 6.86 (s, 1H) 6.70 (br d, J=16.1 Hz, 1H)4.32-4.50 (m, 1H) 3.54-3.70 (m, 1H) 2.85-3.14 (m, 2H) 1.99-2.11 (m, 1H)1.20-1.87 (m, 11H) 1.14 (br d, J=6.0 Hz, 3H)

Compound (M22):

Major rotamer (60%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.66 (br s, 1H) 8.21 (t, J=6.8 Hz, 1H)7.96 (br t, J=6.8 Hz, 1H) 7.79 (d, J=16.2 Hz, 1H) 7.44 (t, J=7.8 Hz, 1H)7.18 (d, J=3.5 Hz, 1H) 7.06 (s, 1H) 6.70 (d, J=16.2 Hz, 1H) 3.98 (br d,J=13.6 Hz, 1H) 3.62-3.81 (m, 1H) 2.92 (br t, J=12.4 Hz, 1H) 1.86-1.99(m, 1H) 1.52-1.86 (m, 7H) 1.18-1.49 (m, 5H) 1.12 (d, J=6.6 Hz, 3H) 0.98(s, 2H)

Minor rotamer (40%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.66 (br s, 1H) 8.21 (t, J=6.8 Hz, 1H)7.96 (br t, J=6.8 Hz, 1H) 7.79 (d, J=16.2 Hz, 1H) 7.44 (t, J=7.8 Hz, 1H)7.20 (d, J=3.5 Hz, 1H) 7.08 (s, 1H) 6.70 (d, J=16.2 Hz, 1H) 4.37-4.49(m, 1H) 3.51 (br d, J=15.7 Hz, 1H) 3.05-3.15 (m, 1H) 1.99-2.11 (m, 1H)1.52-1.86 (m, 7H) 1.18-1.49 (m, 5H) 1.15 (d, J=6.6 Hz, 3H) 0.98 (s, 2H)

Compound (M23)

Major rotamer (60%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.64 (br s, 1H) 8.19 (t, J=6.8 Hz, 1H)7.95 (t, J=6.8 Hz, 1H) 7.78 (d, J=16.2 Hz, 1H) 7.42 (t, J=7.8 Hz, 1H)7.16 (d, J=3.5 Hz, 1H) 7.11 (s, 1H) 6.69 (d, J=16.2 Hz, 1H) 4.28 (quin,J=8.8 Hz, 1H) 3.95-4.10 (m, 1H) 3.65-3.77 (m, 1H) 2.93 (br t, J=12.1 Hz,1H) 2.52-2.61 (m, 2H) 2.31-2.45 (m, 2H) 2.13-2.28 (m, 1H) 1.87-1.99 (m,2H) 1.52-1.87 (m, 4H) 1.20-1.50 (m, 3H) 1.14 (d, J=6.6 Hz, 3H)

Minor rotamer (40%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.64 (br s, 1H) 8.19 (t, J=6.8 Hz, 1H)7.95 (t, J=6.8 Hz, 1H) 7.78 (d, J=16.2 Hz, 1H) 7.42 (t, J=7.8 Hz, 1H)7.18 (d, J=3.5 Hz, 1H) 7.13 (s, 1H) 6.69 (d, J=16.2 Hz, 1H) 4.40-4.52(m, 1H) 4.28 (quin, J=8.8 Hz, 1H) 3.55 (br d, J=15.2 Hz, 1H) 3.07-3.18(m, 1H) 2.52-2.61 (m, 2H) 2.31-2.45 (m, 2H) 2.13-2.28 (m, 1H) 2.01-2.12(m, 1H) 1.87-1.99 (m, 1H) 1.52-1.87 (m, 4H) 1.20-1.50 (m, 3H) 1.16 (d,J=6.6 Hz, 3H)

Compound (M25):

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (d, J=6.3 Hz, 3H) 1.22-1.39 (m, 3H)1.43 (t, J=7.4 Hz, 3H) 1.54-1.84 (m, 4H) 1.91-2.01 (m, 1H) 2.94 (br t,J=12.6 Hz, 1H) 3.26 (q, J=7.6 Hz, 2H) 3.67-3.74 (m, 1H) 4.00 (br d,J=13.6 Hz, 1H) 6.71 (d, J=16.1 Hz, 1H) 7.13 (d, J=7.9 Hz, 1H) 7.20 (dd,J=8.0, 3.3 Hz, 1H) 7.43 (t, J=7.7 Hz, 1H) 7.79 (d, J=16.1 Hz, 1H) 7.97(br t, J=6.8 Hz, 1H) 8.21 (t, J=6.9 Hz, 1H) 12.68 (br s, 1H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.3 Hz, 3H) 1.22-1.39 (m, 3H)1.43 (t, J=7.4 Hz, 3H) 1.54-1.84 (m, 4H) 2.01-2.10 (m, 1H) 3.15 (br dd,J=7.1 Hz, 1H) 3.26 (q, J=7.6 Hz, 2H) 3.54 (br d, J=15.5 Hz, 1H)4.41-4.49 (m, 1H) 6.71 (d, J=16.1 Hz, 1H) 7.13 (d, J=7.9 Hz, 1H) 7.20(dd, J=8.0, 3.3 Hz, 1H) 7.43 (t, J=7.7 Hz, 1H) 7.79 (d, J=16.1 Hz, 1H)7.97 (br t, J=6.8 Hz, 1H) 8.21 (t, J=6.9 Hz, 1H) 12.68 (br s, 1H)

Compound (M26):

Major rotamer: 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.38-1.46 (m, 3H) 1.51-1.60 (m, 3H)2.71-2.79 (m, 1H) 2.84-3.09 (m, 1H) 3.22-3.29 (m, 2H) 3.48-3.54 (m, 1H)5.02-5.07 (m, 1H) 5.59-5.64 (m, 1H) 6.70 (d, J=16.2 Hz, 1H) 7.07-7.26(m, 4H) 7.33 (d, J=7.6 Hz, 1H) 7.43 (t, J=7.6 Hz, 1H) 7.79 (d, J=16.2Hz, 1H) 7.96 (br t, J=7.3 Hz, 1H) 8.22 (br t, J=7.6 Hz, 1H) 12.65 (br s,1H)

Minor rotamer: 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.38-1.46 (m, 3H) 1.51-1.60 (m, 3H)2.71-2.79 (m, 1H) 2.84-3.09 (m, 1H) 3.22-3.29 (m, 2H) 3.48-3.54 (m, 1H)3.91 (br dd, J=14.2, 4.0 Hz, 1H) 4.55-4.61 (m, 1H) 6.70 (d, J=16.2 Hz,1H) 7.07-7.26 (m, 4H) 7.33 (d, J=7.6 Hz, 1H) 7.43 (t, J=7.6 Hz, 1H) 7.79(d, J=16.2 Hz, 1H) 7.96 (br t, J=7.3 Hz, 1H) 8.22 (br t, J=7.6 Hz, 1H)12.65 (br s, 1H

Compound (M27)

Major rotamer (65%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.68 (br s, 1H) 8.24 (br t, J=6.5 Hz,1H) 7.97 (br t, J=6.9 Hz, 1H) 7.79 (br d, J=16.1 Hz, 1H) 7.43 (br t,J=7.7 Hz, 1H) 6.86-7.37 (m, 6H) 6.71 (d, J=16.1 Hz, 1H) 5.60 (q, J=6.5Hz, 1H) 3.82 (br dd, J=13.6, 3.8 Hz, 1H) 3.43-3.53 (m, 1H) 2.62-3.07 (m,2H) 2.67-2.77 (m, 1H) 1.53 (br d, J=6.6 Hz, 3H) 1.23-1.41 (m, 4H)

Minor rotamer (35%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.68 (br s, 1H) 8.24 (br t, J=6.5 Hz,1H) 7.97 (br t, J=6.9 Hz, 1H) 7.79 (br d, J=16.1 Hz, 1H) 7.43 (br t,J=7.7 Hz, 1H) 7.04-7.30 (m, 6H) 6.71 (d, J=16.1 Hz, 1H) 5.60 (q, J=6.5Hz, 1H) 4.97 (q, J=6.4 Hz, 1H) 4.51-4.60 (m, 1H) 2.62-3.07 (m, 3H) 1.56(br d, J=6.9 Hz, 3H) 1.23-1.41 (m, 4H)

Compound (M28)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.44-12.95 (m, 1H) 8.22 (td, J=7.4, 1.3Hz, 1H) 7.92-8.01 (m, 1H) 7.78 (d, J=16.1 Hz, 1H) 7.42 (t, J=7 .7 Hz,1H) 7.16 (d, J=3.5 Hz, 1H) 6.86 (s, 1H) 6.70 (d, J=16.4 Hz, 1H) 3.98 (brd, J=13.6 Hz, 1H) 3.57-3.72 (m, 1H) 2.86-3.01 (m, 2H) 1.87-2.09 (m, 1H)1.49-1.87 (m, 4H) 1.21-1.45 (m, 7H) 1.10 (d, J=6.3 Hz, 3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.44-12.95 (m, 1H) 8.22 (td, J=7.4, 1.3Hz, 1H 7.92-8.01 (m, 1H) 7.78 (d, J=16.1 Hz, 1H) 7.42 (t, J=7 .7 Hz, 1H)7.17 (d, J=3.5 Hz, 1H) 6.87 (s, 1H) 6.70 (d, J=16.4 Hz, 1H) 4.36-4.47(m, 1H) 3.47 (br d, J=15.1 Hz, 1H) 2.86-3.16 (m, 2H) 1.87-2.09 (m, 1H)1.49-1.87 (m, 4H) 1.21-1.45 (m, 7H) 1.14 (d, J=6.6 Hz, 3H)

Compound (N1)

Major rotamer (60%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.21 (br t, J=8.0 Hz, 1H) 7.55-7.64 (m,3H) 7.46 (d, J=15.7 Hz, 1H) 7.08-7.23 (m, 3H) 6.74 (d, J=16.0 Hz, 1H)4.00 (br d, J=11.7 Hz, 1H) 3.47-3.78 (m, 1H) 2.78-3.26 (m, 3H) 1.88-2.12(m, 1H) 1.53-1.84 (m, 4H) 1.42 (t, J=7 .5 Hz, 3H) 1.22-1.35 (m, 3H)1.10-1.19 (m, 3H)

Minor rotamer (40%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.21 (br t, J=8.0 Hz, 1H) 7.55-7.64 (m,3H) 7.46 (d, J=15.7 Hz, 1H) 7.08-7.23 (m, 3H) 6.74 (d, J=16.0 Hz, 1H)4.37-4.50 (m, 1H) 3.47-3.78 (m, 1H) 2.78-3.26 (m, 3H) 1.88-2.12 (m, 1H)1.53-1.84 (m, 4H) 1.42 (t, J=7.5 Hz, 3H) 1.22-1.35 (m, 3H) 1.10-1.19 (m,3H)

Compound (O1)

Major rotamer (60%)

¹H NMR (400 MHz, chloroform-d) δ ppm 8.16 (t, J=8.0 Hz, 1H) 7.17 (t,J=3.6 Hz, 1H) 6.90-7.07 (m, 3H) 4.25 (br d, J=13.2 Hz, 1H) 4.04 (br s,1H) 2.81-3.30 (m, 4H) 2.61-2.70 (m, 1H) 2.08-2.20 (m, 1H) 1.66-2.02 (m,7H) 1.33-1.55 (m, 6H) 1.25 (br t, J=7.0 Hz, 3H)

Minor rotamer (40%)

¹H NMR (400 MHz, chloroform-d) δ ppm 8.16 (t, J=8.0 Hz, 1H) 7.17 (t,J=3.6 Hz, 1H) 6.90-7.07 (m, 3H) 4.60-4.73 (m, 1H) 3.89 (br d, J=15.6 Hz,1H) 2.81-3.30 (m, 4H) 2.61-2.70 (m, 1H) 2.08-2.20 (m, 1H) 1.66-2.02 (m,7H) 1.33-1.55 (m, 6H) 1.25 (br t, J=7.0 Hz, 3H)

Compound (02):

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.12 (t, J=6.3 Hz 3H) 1.22-1.38 (m, 3H)1.39-1.47 (m, 1H) 1.42 (t, J=7.6 Hz 3H) 1.50-2.11 (m, 7H) 2.41 (br s,1H) 2.93 (br t, J=12.8 Hz, 1H) 3.24 (q, J=7.3 Hz 2H) 3.66-3.74 (m, 1H)3.99 (br d, J=13.2 Hz, 1H) 7.06-7.11 (m, 2H) 7.13-7.23 (m, 2H) 8.05 (t,J=8.0 Hz, 1H) 12.6 (br s, 1H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (d, J=6.3 Hz 3H) 1.22-1.38 (m, 3H)1.39-1.47 (m, 1H) 1.42 (t, J=7.6 Hz 3H) 1.50-2.11 (m, 7H) 2.41 (br s,1H) 3.08-3.18 (m, 1H) 3.24 (q, J=7.3 Hz 2H) 3.53 (br d, J=14.2 Hz 1H)4.40-4.48 (m, 1H7.06-7.11 (m, 2H) 7.13-7.23 (m, 2H) 8.05 (t, J=8.0 Hz,1H) 12.6 (br s, 1H)

Compound (O3):

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.11-1.18 (m, 3H) 1.21-1.38 (m, 3H)1.40-1.49 (m, 2H) 1.55-1.61 (m, 1H) 1.63-1.83 (m, 3H) 1.84-1.98 (m, 3H)2.00-2.10 (m, 1H) 2.12-2.24 (m, 1H) 2.32-2.47 (m, 3H) 2.52-2.60 (m, 3H)2.93 (t, J=12.3 Hz, 1H) 3.70 (dt, J=9.8, 6.3 Hz, 1H) 4.00 (br d, J=13.6Hz, 1H) 4.23-4.32 (m, 1H) 7.10-7.11 (dd, J=7.9, 0.6 Hz, 1H) 7.12-7.15(dd, J=7.9, 3.5 Hz, 1H) 7.18-7.21 (dt, J=7.6, 1.3 Hz, 1H) 7.27 (t, J=7.7Hz, 1H) 7.98 (t, J=7.2 Hz, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.11-1.18 (m, 3H) 1.21-1.38 (m, 3H)1.40-1.49 (m, 2H) 1.55-1.61 (m, 1H) 1.63-1.83 (m, 3H) 1.84-1.98 (m, 3H)2.12-2.24 (m, 1H) 2.32-2.47 (m, 3H) 2.52-2.60 (m, 3H) 3.07-3.20 (m, 1H)3.54 (br d, J=15.5 Hz, 1H) 4.23-4.32 (m, 1H) 4.45 (dt, J=12.1, 6.1 Hz,1H) 7.10-7.11 (dd, J=7.9, 0.6 Hz, 1H) 7.12-7.15 (dd, J=7.9, 3.5 Hz, 1H)7.18-7.21 (dt, J=7.6, 1.3 Hz, 1H) 7.27 (t, J=7.7 Hz, 1H) 7.98 (t, J=7.2Hz, 1H)

Compound (W1):

Major rotamer (60%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12 (d, J=6.6 Hz, 3H) 1.20-1.36 (m, 3H)1.40 (t, J=7.6 Hz, 3H) 1.54-1.83 (m, 4H) 1.85-1.99 (m, 1H) 2.92 (br t,J=12.4 Hz, 1H) 3.22 (q, J=7.6 Hz, 2H) 3.51-3.60 (m, 1H) 3.66-3.76 (m,1H) 3.93-4.02 (m, 3H) 4.07-4.14 (m, 2H) 6.37-6.44 (m, 2H) 6.93 (t, J=4.7Hz, 1H) 7.00 (d, J=7.2 Hz, 1H) 7.96 (t, J=8.7 Hz, 1H) 12.67 (br s, 1H)

Minor rotamer (40%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.13 (d, J=6.6 Hz, 3H) 1.20-1.36 (m, 3H)1.40 (t, J=7.6 Hz, 3H) 1.54-1.83 (m, 4H) 2.00-2.10 (m, 1H) 3.07-3.17 (m,1H) 3.22 (q, J=7.6 Hz, 2H) 3.51-3.60 (m, 2H) 3.93-4.02 (m, 2H) 4.07-4.14(m, 2H) 4.38-4.49 (m, 1H) 6.37-6.44 (m, 2H) 6.93 (t, J=4.7 Hz, 1H) 7.00(d, J=7.2 Hz, 1H) 7.96 (t, J=8.7 Hz, 1H) 12.67 (br s, 1H

Compound (W4)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.12 (d, J=6.1 Hz, 3H) 1.22-1.36 (m, 4H)1.41 (t, J=7.4 Hz, 3H) 1.55-1.67 (m, 3H) 1.68-1.82 (m, 4H) 1.90-1.98 (m,2H) 2.90-2.97 (m, 2H) 3.09-3.14 (m, 1H) 3.20-3.26 (m, 2H) 3.64-3.67 (brd, J=12.9 Hz, 1H) 3.68-3.73 (m, 1H) 3.80-3.84 (dd, J=9.8, 3.2 Hz, 1H)3.98-4.01 (br d, J=12.9 Hz, 1H) 6.85-6.89 (dd, J=13.2, 2.2 Hz, 1H)6.91-6.94 (dd, J=6.3, 2.3 Hz, 1H) 6.95-6.97 (m, 1H) 7.02 (d, J=8.5 Hz,1H) 12.34-12.54 (m, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (d, J=6.6 Hz, 3H) 1.22-1.36 (m, 4H)1.41 (t, J=7.4 Hz, 3H) 1.55-1.67 (m, 3H) 1.68-1.82 (m, 4H) 1.90-1.98 (m,1H) 2.00-2.10 (m, 1H) 2.90-2.97 (m, 2H) 3.09-3.14 (m, 1H) 3.20-3.26 (m,2H) 3.52-3.56 (br d, J=15.1 Hz, 1H) 3.64-3.67 (br d, J=12.9 Hz, 1H)3.80-3.84 (dd, J=9.8, 3.2 Hz, 1H) 4.42-4.47 (m, 1H) 6.85-6.89 (dd,J=13.2, 2.2 Hz, 1H) 6.91-6.94 (dd, J=6.3, 2.3 Hz, 1H) 6.95-6.97 (m, 1H)7.02 (d, J=8.5 Hz, 1H) 12.34-12.54 (m, 1H)

Compound (WS)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09-1.15 (m, 3H) 1.15-1.44 (m, 3H) 1.52(t,

J=7.6 Hz, 3H) 1.44-1.85 (m, 7H) 1.91-2.00 (m, 2H) 2.52-2.57 (m, 1H)2.87-3.01 (m, 2H) 3.08-3.17 (m, 1H) 3.18-3.27 (q, J=7.6, 15.2 Hz, 2H)3.50-4.04 (m, 4H) 6.83-7.02 (m, 4H) 7.97 (t, J=9.1 Hz, 1H) 12.17-12.46(m, 1H)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09-1.15 (m, 3H) 1.15-1.44 (m, 3H)1.52(t, J=7.6 Hz, 3H) 1.44-1.85 (m, 7H) 1.91-2.00 (m, 1H) 2.00-2.10 (m, 1H)2.52-2.57 (m, 1H) 2.87-3.01 (m, 2H) 3.08-3.17 (m, 1H) 3.18-3.27 (q,J=7.6, 15.2 Hz, 2H) 3.50-4.04 (m, 3H) 4.39-4.49 (m, 1H) 6.83-7.02 (m,4H) 7.97 (t, J=9.1 Hz, 1H) 12.17-12.46 (m, 1H)

Compound (W6)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.11-1.20 (m, 3H) 1.21-1.36 (m, 3H)1.36-1.47 (m, 3H) 1.52-1.84 (m, 4H) 1.89-2.11 (m, 1H) 2.14-2.32 (m, 2H)2.92 (br t, J=12.6 Hz, 1H) 3.18-3.28 (m, 3H) 3.36-3.42 (m, 2H) 3.44-3.57(m, 2H) 3.66-3.74 (m, 1H) 3.99 (br d, J=12.9 Hz, 1H) 6.47 (br d, J=14.5Hz, 1H) 6.54 (br d, J=8.5 Hz, 1H) 6.93 (br dd, J=7.3, 3.5 Hz, 1H) 7.00(br d, J=8.5 Hz, 1H) 7.98 (br t, J=8.7 Hz, 1H) 12.58 (br s, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.11-1.20 (m, 3H) 1.21-1.36 (m, 3H)1.36-1.47 (m, 3H) 1.52-1.84 (m, 4H) 1.89-2.11 (m, 1H) 2.14-2.32 (m, 2H)3.12 (m, 1H) 3.18-3.28 (m, 3H) 3.36-3.42 (m, 2H) 3.44-3.57 (m, 3H) 4.44(br d, J=6.0 Hz, 1H) 6.47 (br d, J=14.5 Hz, 1H) 6.54 (br d, J=8.5 Hz,1H) 6.93 (br dd, J=7.3, 3.5 Hz, 1H) 7.00 (br d, J=8.5 Hz, 1H) 7.98 (brt, J=8.7 Hz, 1H) 12.58 (br s, 1H)

Compound (W7)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.11-1.20 (m, 3H) 1.21-1.36 (m, 3H)1.36-1.47 (m, 3H) 1.52-1.84 (m, 4H) 1.89-2.11 (m, 1H) 2.14-2.32 (m, 2H)2.92 (br t, J=12.6 Hz, 1H) 3.18-3.28 (m, 3H) 3.36-3.42 (m, 2H) 3.44-3.57(m, 2H) 3.66-3.74 (m, 1H) 3.99 (br d, J=12.9 Hz, 1H) 6.47 (br d, J=14.5Hz, 1H) 6.54 (br d, J=8.5 Hz, 1H) 6.93 (br dd, J=7.3, 3.5 Hz, 1H) 7.00(br d, J=8.5 Hz, 1H) 7.98 (br t, J=8.7 Hz, 1H) 12.58 (br s, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.11-1.20 (m, 3H) 1.21-1.36 (m, 3H)1.36-1.47 (m, 3H) 1.52-1.84 (m, 4H) 1.89-2.11 (m, 1H) 2.14-2.32 (m, 2H)3.12 (m, 1H) 3.18-3.28 (m, 3H) 3.36-3.42 (m, 2H) 3.44-3.57 (m, 3H) 4.44(br d, J=6.0 Hz, 1H) 6.47 (br d, J=14.5 Hz, 1H) 6.54 (br d, J=8.5 Hz,1H) 6.93 (br dd, J=7.3, 3.5 Hz, 1H) 7.00 (br d, J=8.5 Hz, 1H) 7.98 (brt, J=8.7 Hz, 1H) 12.58 (br s, 1H)

Compound (W8)

Major rotamer (60%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.76 (br s, 1H) 9.19 (s, 1H) 8.32 (t,J=8.6 Hz, 1H) 8.15 (s, 1H) 8.05 (dd, J=12.6, 2.0 Hz, 1H) 7.99 (dd,J=8.8, 2.3 Hz, 1H) 7.14 (d, J=3.0 Hz, 1H) 6.85 (s, 1H) 3.97 (br d,J=13.1 Hz, 1H) 3.58-3.71 (m, 1H) 2.85-3.03 (m, 2H) 1.85-2.13 (m, 1H)1.49-1.85 (m, 4H) 1.22-1.44 (m, 7H) 1.10 (d, J=6.1 Hz, 3H)

Minor rotamer (40%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.76 (br s, 1H) 9.19 (s, 1H) 8.32 (t,J=8.6 Hz, 1H) 8.15 (s, 1H) 8.05 (dd, J=12.6, 2.0 Hz, 1H) 7.99 (dd,J=8.8, 2.3 Hz, 1H) 7.16 (d, J=3.5 Hz, 1H) 6.85 (s, 1H) 4.36-4.47 (m, 1H)3.47 (br d, J=14.7 Hz, 1H) 2.85-3.17 (m, 2H) 1.85-2.13 (m, 1H) 1.49-1.85(m, 4H) 1.22-1.44 (m, 7H) 1.14 (d, J=6.6 Hz, 3H)

Compound (W9)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.78 (br s, 1H) 9.19 (s, 1H) 8.30 (t,J=8.5 Hz, 1H) 8.16 (s, 1H) 7.90-8.09 (m, 2H) 7.05-7.22 (m, 2H) 4.30(quin, J=8.7 Hz, 1H) 4.01 (br d, J=13.2 Hz, 1H) 3.66-3.83 (m, 1H) 2.94(br t, J=12.5 Hz, 1H) 2.53-2.61 (m, 2H) 2.34-2.44 (m, 2H) 2.13-2.29 (m,1H) 1.88-2.13 (m, 2H) 1.52-1.86 (m, 4H) 1.21-1.51 (m, 3H) 1.14 (d, J=6.3Hz, 3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.78 (br s, 1H) 9.19 (s, 1H) 8.30 (t,J=8.5 Hz, 1H) 8.16 (s, 1H) 7.90-8.09 (m, 2H) 7.05-7.22 (m, 2H) 4.38-4.57(m, 1H) 4.30 (quin, J=8.7 Hz, 1H) 3.54 (br d, J=15.4 Hz, 1H) 3.08-3.16(m, 1H) 2.53-2.61 (m, 2H) 2.34-2.44 (m, 2H) 2.13-2.29 (m, 1H) 1.88-2.13(m, 2H) 1.52-1.86 (m, 4H) 1.21-1.51 (m, 3H) 1.16 (d, J=6.3 Hz, 3H)

Compound (W10)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.79 (br s, 1H) 9.20 (s, 1H) 8.31 (t,J=8.4 Hz, 1H) 8.17 (s, 1H) 8.05 (dd, J=12.5, 2.0 Hz, 1H) 8.00 (dd,J=8.5, 1.9 Hz, 1H) 7.18 (d, J=3.2 Hz, 1H) 7.08 (s, 1H) 3.99 (br d,J=13.2 Hz, 1H) 3.63-3.76 (m, 1H) 2.93 (br t, J=12.5 Hz, 1H) 1.90-2.11(m, 1H) 1.54-1.85 (m, 7H) 1.20-1.50 (m, 5H) 1.13 (d, J=6.3 Hz, 3H) 1.00(s, 2H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.79 (br s, 1H) 9.20 (s, 1H) 8.31 (t,J=8.4 Hz, 1H) 8.17 (s, 1H) 8.05 (dd, J=12.5, 2.0 Hz, 1H) 8.00 (dd,J=8.5, 1.9 Hz, 1H) 7.20 (d, J=3.5 Hz, 1H) 7.09 (s, 1H) 4.38-4.43 (m, 1H)3.51 (br d, J=15.4 Hz, 1H) 3.08-3.16 (m, 1H) 1.90-2.11 (m, 1H) 1.54-1.85(m, 7H) 1.20-1.50 (m, 5H) 1.15 (d, J=6.3 Hz, 3H) 1.00 (s, 2H)

Compound (W11)

Major rotamer 55%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (d, J=6.3 Hz, 3H) 1.21-1.35 (m, 3H)1.41 (t, J=7.4 Hz, 3H) 1.54-1.66 (m, 2H) 1.68-1.84 (m, 3H) 1.92-1.99 (m,1H) 2.43 (br s, 2H) 2.92 (br t, J=12.5 Hz, 1H) 3.19-3.26 (m, 2H) 3.50(t, J=5.7 Hz, 2H) 3.67-3.75 (m, 1H) 3.99 (br d, J=2.8 Hz, 2H) 6.87-6.91(m, 1H) 6.93 (br s, 1H) 6.96 (dt, J=7.1, 3.7 Hz, 2H) 7.02 (d, J=8.5 Hz,1H) 8.01 (t, J=8.8 Hz, 1H) 12.4 (s, 1H)

Minor rotamer 45%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (d, J=6.3 Hz, 3H) 1.21-1.35 (m, 3H)1.41 (t, J=7.4 Hz, 3H) 1.54-1.66 (m, 1H) 1.68-1.84 (m, 3H) 2.01-2.10 (m,1H) 2.43 (br s, 2H) 3.09-3.17 (m, 1H) 3.19-3.26 (m, 2H) 3.50 (t, J=5.7Hz, 2H) 3.54 (br d, J=15.5 Hz, 1H) 3.99 (br d, J=2.8 Hz, 2H) 4.44 (dt,J=12.0, 6.0 Hz, 1H) 6.87-6.91 (m, 1H) 6.93 (br s, 1H) 6.96 (dt, J=7.1,3.7 Hz, 2H) 7.02 (d, J=8.5 Hz, 1H) 8.01 (t, J=8.8 Hz, 1H) 12.4 (s, 1H)

Compound (W12)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08-1.32 (m, 6H) 1.32-1.45 (m, 3H)1.53-1.82 (m, 4H) 1.85-2.09 (m, 1H) 2.39-2.45 (m, 1H) 2.78 (dd, J=15.4,4.8 Hz, 1H) 2.91 (t, J=12.6 Hz, 1H) 3.00-3.15 (m, 2H) 3.15-3.26 (m, 2H)3.41-3.59 (m, 3H) 3.60-3.74 (m, 2H) 3.99 (br d, J=12.6 Hz, 1H) 6.47 (d,J=14.7 Hz, 1H) 6.55 (d, J=8.6 Hz, 1H) 6.60(s, 1H) 6.86-6.94 (m, 1H) 6.98(d, J=7.6 Hz, 1H) 7.96 (t, J=8.6 Hz, 1H) 12.15-12.44 (s, 1H)

Minor rotamers 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08-1.32 (m, 6H) 1.32-1.45 (m, 3H)1.53-1.82 (m, 4H) 1.85-2.09 (m, 1H) 2.39-2.45 (m, 1H) 2.78 (dd, J=15.4,4.8 Hz, 1H) 2.91 (t, J=12.6 Hz, 1H) 3.00-3.15 (m, 2H) 3.15-3.26 (m, 2H)3.41-3.59 (m, 3H) 3.60-3.74 (m, 2H) 4.39-4.48 (m, 1H) 6.47 (d, J=14.7Hz, 1H) 6.55 (d, J=8.6 Hz, 1H) 6.60 (s, 1H) 6.86-6.94 (m, 1H) 6.98 (d,J=7.6 Hz, 1H) 7.96 (t, J=8.6 Hz, 1H) 12.15-12.44 (s, 1H)

Compound (X1):

Major rotamer (60%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.13 (d, J=6.1 Hz, 3H) 1.09-1.51 (m, 4H)1.43 (t, J=7.6 Hz, 3H) 1.55-1.83 (m, 4H) 1.89-1.99 (m, 1H) 2.93 (br t,J=12.6 Hz, 1H) 3.25 (d, J=7.6 Hz, 2H) 3.67-3.75 (m, 1H) 4.00 (br d,J=14.7 Hz, 1H) 6.74 (s, 1H) 7.13 (d, J=6.1 Hz, 1H) 7.20 (m, 1H) 7.79 (d,J=7.1 Hz, 1H) 7.87 (d, J=12.1 Hz, 1H) 8.30 (t, J=7.8 Hz, 1H) 11.57 (brs, 1H)

Minor rotamer (40%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (d, J=6.6 Hz, 3H) 1.09-1.51 (m, 4H)1.43 (t, J=7.6 Hz, 3H) 1.55-1.83 (m, 4H) 2.02-2.10 (m, 1H) 3.10-3.20 (m,1H) 3.25 (d, J=7.6 Hz, 2H) 3.50-3.57 (m, 1H) 4.41-4.48 (m, 1H) 6.74 (s,1H) 7.13 (d, J=6.1 Hz, 1H) 7.20 (m, 1H) 7.79 (d, J=7.1 Hz, 1H) 7.87 (d,J=12.1 Hz, 1H) 8.30 (t, J=7.8 Hz, 1H) 11.57 (br s, 1H)

Compound (F41)

Major rotamer (65%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.52 (br s, 1H) 9.19 (d, J=1.9 Hz, 1H)8.39 (dd, J=8.2, 1.9 Hz, 1H) 8.30-8.35 (m, 1H) 8.26 (d, J=8.2 Hz, 1H)8.17-8.23 (m, 2H) 7.21 (d, J=3.5 Hz, 1H) 7.14 (s, 1H-4.01 (br d, J=13.2Hz, 1H) 3.63-3.73 (m, 1H) 3.09-3.23 (m, 2H) 2.94 (br t, J=12.6 Hz, 1H)2.43-2.48 (m, 1H) 1.90-1.99 (m, 1H) 1.50-1.86 (m, 4H) 1.22-1.49 (m, 3H)1.12 (d, J=6.3 Hz, 3H) 0.97-1.04 (m, 6H)

Minor rotamer (35%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.52 (br s, 1H) 9.19 (d, J=1.9 Hz, 1H)8.39 (dd, J=8.2, 1.9 Hz, 1H) 8.30-8.35 (m, 1H) 8.26 (d, J=8.2 Hz, 1H)8.17-8.23 (m, 2H) 7.22 (d, J=3.5 Hz, 1H) 7.16 (s, 1H) 4.41-4.49 (m, 1H)3.54 (br d, J=15.8 Hz, 1H) 3.09-3.23 (m, 3H) 2.43-2.48 (m, 1H) 2.02-2.11(m, 1H) 1.50-1.86 (m, 4H) 1.22-1.49 (m, 3H) 1.16 (d, J=6.3 Hz, 3H)0.97-1.04 (m, 6H)

Compound (F42)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.79 (br s, 1H) 7.58 (t, J=7.1 Hz, 1H)7.01-7.13 (m, 3H) 4.39-4.50 (m, 1H) 4.30 (dd, J=10.7, 7.3 Hz, 1H) 3.99(br d, J=12.9 Hz, 1H) 3.65-3.76 (m, 1H) 3.23 (q, J=7.3 Hz, 2H) 3.01-3.15(m, 3H) 2.93 (br t, J=12.5 Hz, 1H) 1.89-1.99 (m, 1H) 1.53-1.86 (m, 4H)1.41 (t, J=7.4 Hz, 3H) 1.19-1.38 (m, 3H) 1.12 (d, J=6.3 Hz, 3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.79 (br s, 1H) 7.58 (t, J=7.1 Hz, 1H)7.01-7.13 (m, 3H) 4.39-4.50 (m, 2H) 4.30 (dd, J=10.7, 7.3 Hz, 1H) 3.54(br d, J=14.5 Hz, 1H) 3.23 (q, J=7.3 Hz, 2H) 3.01-3.15 (m, 4H) 2.01-2.11(m, 1H) 1.53-1.86 (m, 4H) 1.41 (t, J=7.4 Hz, 3H) 1.19-1.38 (m, 3H) 1.15(d, J=6.3 Hz, 3H)

Compound (F43)

Major rotamer 58%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (d, J=6.3 Hz, 3H) 1.21-1.38 (m, 3H)1.43 (t, J=7.4 Hz, 3H) 1.54-1.80 (m, 4H) 1.94 (m, 1H) 2.94 (t, J=12.6Hz, 1H) 3.22-3.30 (m, 2H) 3.67-3.74 (m, 1H) 4.00 (d, J=13.2 Hz, 1H) 7.14(d, J=7.6 Hz, 1H) 7.22 (dd, J=8.2, 3.5 Hz, 1H) 8.02 (d, J=5.9 Hz, 1H)8.04 (s, 1H) 8.34 (t, J=8.0 Hz, 1H) 8.48 (s, 1H) 13.75 (br s, 1H)

Minor rotamer 42%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.3 Hz, 3H) 1.21-1.38 (m, 3H)1.43 (t, J=7.4 Hz, 3H) 1.54-1.80 (m, 4H) 2.00-2.10 (m, 1H) 3.08-3.18 (m,1H) 3.22-3.30 (m, 2H) 3.54 (d, J=15.5 Hz, 1H) 4.44 (dt, J=12.0, 6.0 Hz,1H) 7.14 (d, J=7.6 Hz, 1H) 7.22 (dd, J=8.2, 3.5 Hz, 1H) 8.02 (d, J=5.9Hz, 1H) 8.04 (s, 1H) 8.34 (t, J=8.0 Hz, 1H) 8.48 (s, 1H) 13.75 (br s,1H)

Compound (F44)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (d, J=6.3 Hz, 3H) 1.24-1.40 (m, 3H)1.44 (t, J=7.3 Hz, 3H)1.55-1.85 (m, 4H) 1.95-2.11 (m, 1H) 2.94 (br t,J=12.6 Hz, 1H) 3.24-3.30 (q, J=7.25 Hz , 2H) 3.68-3.76 (m, 1H) 4.01 (brd, J=13.2 Hz, 1H) 7.12 (d, J=8.8 Hz, 1H) 7.20 (dd, J=7.9, 3.2 Hz, 1H)7.76 (d, J=8.5 Hz, 1H) 7.86 (s, 1H) 8.30 (t, J=8.0 Hz, 1H) 13.79-14.01(m, 1H)

Minor rotamers 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 (d, J=6.3 Hz, 3H) 1.24-1.40 (m, 3H)1.44 (t, J=7.3 Hz, 3H)1.55-1.85 (m, 4H) 1.95-2.11 (m, 1H) 3.10-3.18 (m,1H) 3.24-3.30 (q, J=7.3 Hz , 2H) 3.52-3.59 (m, 1H) 4.42-4.49 (m, 1H)7.12 (d, J=8.8 Hz, 1H) 7.20 (dd, J=7.9, 3.2 Hz, 1H) 7.76 (d, J=8.5 Hz,1H) 7.86 (s, 1H) 8.30 (t, J=8.0 Hz, 1H) 13.79-14.01 (m, 1H)

Compound (F45)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (d, J=6.6 Hz, 3H) 1.20-1.38 (m, 3H)1.46 (br t, J=7.6 Hz, 3H) 1.54-1.85 (m, 4H) 1.89-2.14 (m, 1H) 2.89-3.01(m, 1H)3.22-3.37 (m, 2H) 3.67-3.84 (m, 1H) 3.94-4.10 (m, 1H) 7.15 (d,J=6.1 Hz, 1H) 7.38 (dd, J=8.1, 3.0 Hz, 1H) 8.03 (br d, J=8.6 Hz, 1H)8.19 (d, J=8.6 Hz, 1H) 8.47 (br t, J=7.6 Hz, 1H) 8.62 (br d, J=8.6 Hz,1H) 13.54 (br s, 1H)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.6 Hz, 3H) 1.20-1.38 (m, 3H)1.46 (br t, J=7.6 Hz, 3H) 1.54-1.85 (m, 4H) 1.89-2.14 (m, 1H) 3.09-3.20(m, 1H) 3.22-3.37 (m, 2H) 3.53-3.64 (m, 1H) 4.38-4.56 (m, 1H) 7.15 (d,J=6.1 Hz, 1H) 7.38 (dd, J=8.1, 3.0 Hz, 1H) 8.03 (br d, J=8.6 Hz, 1H)8.19 (d, J=8.6 Hz, 1H) 8.47 (br t, J=7.6 Hz, 1H) 8.62 (br d, J=8.6 Hz,1H) 13.54 (br s, 1H)

Compound (F46)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (d, J=6.5 Hz, 3H) 1.22-1.36 (m, 3H)1.41 (t, J=7.4 Hz, 3H) 1.54-1.66 (m, 1H) 1.66-1.84 (m, 2H) 1.94-2.10 (m,1H) 2.35-2.39 (m, 1H) 2.93 (t, J=12.6 Hz, 1H) 3.21-3.27 (m, 2H)3.66-3.74 (m, 1H) 3.99 (br d, J=13.9 Hz, 1H) 5.04 (d, J=1.3 Hz, 2H) 6.93(d, J=8.5 Hz, 1H) 7.07-7.10 (m, 2H) 7.55 (s, 1H) 8.06 (t, J=8.5 Hz, 1H)13.10-13.30 (m, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.5 Hz, 3H) 1.22-1.36 (m, 3H)1.41 (t, J=7.4 Hz, 3H) 1.54-1.66 (m, 1H) 1.66-1.84 (m, 2H) 1.94-2.10 (m,1H) 2.35-2.39 (m, 1H) 3.10-3.17 (m, 1H) 3.21-3.27 (m, 2H) 3.53 (br d,J=15.5 Hz, 1H) 4.44 (dt, J=11.7, 5.95 Hz, 1H) 5.04 (d, J=1.3 Hz, 2H)6.93 (d, J=8.5 Hz, 1H) 7.07-7.10 (m, 2H) 7.55 (s, 1H) 8.06 (t, J=8.5 Hz,1H) 13.10-13.30 (m, 1H)

Compound (F47)

Major rotamer 65%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (d, J=6.3 Hz, 3H) 1.20-1.35 (m, 3H)1.36-1.48 (m, 3H) 1.54-1.85 (m, 4H) 1.87-2.18 (m, 5H) 2.21-2.40 (m, 4H)2.87-3.00 (m, 2H) 3.21-3.27 (m, 2H) 3.39-3.50 (m, 1H) 3.66-3.74 (m, 1H)3.99 (br d, J=13.2 Hz, 1H) 7.05-7.11 (m, 2H) 7.18-7.24 (m, 2H) 8.07 (t,J=8.0 Hz, 1H) 11.91-12.80 (m, 1H)

Minor rotamer 45%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (d, J=6.3 Hz, 3H) 1.20-1.35 (m, 3H)1.36-1.48 (m, 3H) 1.54-1.85 (m, 4H) 1.87-2.18 (m, 5H) 2.21-2.40 (m, 4H)2.87-3.00 (m, 1H) 3.06-3.19 (m, 1H) 3.21-3.27 (m, 2H) 3.39-3.50 (m, 1H)3.54 (br d, J=15.5 Hz, 1H) 4.40-4.50 (m, 1H) 7.05-7.11 (m, 2H) 7.18-7.24(m, 2H) 8.07 (t, J=8.0 Hz, 1H) 11.91-12.80 (m, 1H)

Compound (F48)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.97 (s, 2H) 1.09-1.16 (m, 3H) 1.18-1.35(m, 5H) 1.55-1.82 (m, 7H) 1.89-1.99 (m, 1H) 2.91 (br t, J=12.1 Hz, 1H)3.64-3.75 (m, 1H) 3.98 (br d, J=13.6 Hz, 1H) 4.80 (s, 2H) 6.96-1.73 (m,5H) 8.08 (t, J=8.8 Hz, 1H) 13.1 (br s, 1H)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.97 (s, 2H) 1.09-1.16 (m, 3H) 1.18-1.35(m, 4H) 1.38-1.49 (m, 1H) 1.55-1.82 (m, 7H) 1.99-2.10 (m, 1H) 3.06-3.15(m, 1H) 3.51 (br d, J=14.7 Hz, 1H) 4.38-4.47 (m, 1H) 4.80 (s, 2H)6.96-1.73 (m, 5H) 8.08 (t, J=8.8 Hz, 1H) 13.1 (br s, 1H)

Compound (F49)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.06 (s, 2H) 1.17-1.23 (m, 3H) 1.26-1.44(m, 4H) 1.46-1.55 (m, 1H) 1.64-1.73 (m, 4H) 1.75-1.88 (m, 3H) 1.94-2.06(m, 1H) 3.00 (t, J=12.5 Hz, 1H) 3.73-3.80 (m, 1H) 4.05 (br d, J=7.6, 3.2Hz, 1H) 7.20 (d, J=6.0 Hz, 1H) 7.39 (dd, J=7.6, 3.2 Hz, 1H) 7.93 (d,J=8.5 Hz, 1H) 8.20 (t, J=7.1 Hz, 1H) 8.85 (s, 1H) 13.53 (br s, 1H

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.06 (s, 2H) 1.17-1.23 (m, 3H) 1.26-1.44(m, 5H) 1.64-1.73 (m, 5H) 1.75-1.88 (m, 2H) 2.06-2.28 (m, 1H) 3.15-3.22(m, 1H) 3.43-3.60 (m, 1H) 4.49 (dt, J=12.0, 6.0 Hz, 1H) 7.20 (d, J=6.0Hz, 1H) 7.39 (dd, J=7.6, 3.2 Hz, 1H) 7.93 (d, J=8.5 Hz, 1H) 8.20 (t,J=7.1 Hz, 1H) 8.85 (s, 1H) 13.53 (br s, 1H)

Compound (F55)

Major rotamer 65%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40-1.48 (m, 3H) 1.55 (d, J=6.6 Hz, 3H)2.61-2.89 (m, 2H) 3.25-3.31 (m, 2H) 3.37-3.49 (m, 1H) 3.97 (br dd,J=13.4, 4.8 Hz, 1H) 5.70-5.77 (m, 1H) 6.85-6.89 (m, 1H) 7.18-7.24 (m,1H) 7.27 (s, 1H) 7.37-7.45 (m, 1H) 8.17-8.40 (m, 5H) 9.19 (d, J=2.0 Hz,1H) 13.5 (br s, 1H)

Minor rotamer 35%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40-1.48 (m, 3H) 1.61 (d, J=6.6 Hz, 3H)2.61-2.89 (m, 2H) 3.16-3.25 (m, 1H) 3.25-3.31 (m, 2H) 4.63-4.70 (m, 1H)5.19-5.26 (m, 1H) 6.85-6.89 (m, 1H) 7.18-7.24 (m, 1H) 7.27 (s, 1H)7.37-7.45 (m, 1H) 8.17-8.40 (m, 5H) 9.19 (d, J=2.0 Hz, 1H) 13.5 (br s,1H)

Compound (F56)

Major rotamer 65%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41-1.49 (m, 3H) 1.49-1.54 (d, J=6.6Hz, 3H) 3.25-3.30 (m, 2H) 3.67-3.80 (m, 1H) 3.86 (td, J=11.59, 3.63 Hz,1H) 3.93-4.03 (m, 1H) 4.21 (br d, J=12.93 Hz, 1H) 5.66-5.73 (m, 1H) 6.06(br d, J=3.15 Hz, 1H) 6.12 (d, J=3.47 Hz, 1H) 7.22-7.33 (m, 3H)8.17-8.30 (m, 3H) 8.32-8.42 (m, 2H) 9.20 (s, 1H) 13.50 (br s, 1H)

Minor rotamer 35%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41-1.49 (m, 3H) 1.54-1.60 (d, J=6.31Hz, 3H) 3.25-3.30 (m, 2H) 3.37-3.55 (m, 1H) 3.67-3.80 (m, 1H) 4.08-4.16(m, 1H) 4.76 (br d, J=13.24 Hz, 1H) 5.22 (m, 1H) 5.85 (br d, J=3.5 Hz,1H) 6.06 (br d, J=3.15 Hz, 1H) 7.22-7.33 (m, 3H) 8.17-8.30 (m, 3H)8.32-8.42 (m, 2H) 9.20 (s, 1H) 13.50 (br s, 1H)

Compound (F57)

Major rotamers 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (d, J=6.6 Hz, 1H) 1.22-1.38 (m, 4H)1.41-1.54 (m, 5H) 1.61-1.89 (m, 3H) 2.27-2.32 (m, 1H) 2.66-2.75 (m, 1H)3.49 (dd, J=11.9, 3.8 Hz, 1H) 3.58-3.63 (m, 1H) 3.95 (dd, J=12.4, 7.8Hz, 1H) 4.10-4.16 (m, 1H) 7.21-7.27 (m, 2H) 8.15-8.23 (m, 2H) 8.25 (d,J=8.6 Hz, 1H) 8.31-8.40 (m, 2H) 9.18 (s, 1H) 13.35-13.57 (m, 1H)

Minor rotamers 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (d, J=6.6 Hz, 1H) 1.22-1.38 (m, 4H)1.41-1.54 (m, 5H) 1.61-1.89 (m, 3H) 2.27-2.32 (m, 1H) 2.75-2.83 (m, 1H)3.49 (dd, J=11.9, 3.8 Hz, 1H) 3.58-3.63 (m, 1H) 3.95 (dd, J=12.4, 7.8Hz, 1H) 4.19-4.25 (m, 1H) 7.21-7.27 (m, 2H) 8.15-8.23 (m, 2H) 8.25 (d,J=8.6 Hz, 1H) 8.31-8.40 (m, 2H) 9.18 (s, 1H) 13.35-13.57 (m, 1H)

Compound (F58)

Major rotamer 65%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.41-1.51 (m, 6H) 2.33 (s, 1H) 2.80-2.82(m, 1H) 2.90-2.97 (m, 1H) 3.28-3.31 (q, 2H) 3.40-3.47 (m, 1H) 3.98-4.01(dd, J=13.9, 4.7 Hz, 1H) 5.44-5.48 (q, J=12.9, 6.3 Hz, 1H, 6.70 (s 1H)7.19-7.23 (m,1H) 7.27-2.28 (m, 1H) 8.19-8.27 (m , 3H) 8.34-8.40 (m, 2H)9.19 (d, J=1.9 Hz, 1H, 13.50-13.60 (br s, 1H)

Minor rotamer 35%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.41-1.51 (m, 6H) 2.33 (s, 1H) 2.66 (m,1H) 2.69 (m, 1H) 3.20-3.26 (m, 1H) 3.28-3.31 (q, 2H) 4.70-4.72 (m, 1H,4.86-4.90 (q, J=14.2, 7.6 Hz, 1H) 6.67 (s, 1H) 7.19-7.23 (m,1H)7.27-2.28 (m, 1H) 8.19-8.27 (m , 3H) 8.34-8.40 (m, 2H) 9.19 (d, J=1.9Hz, 1H, 13.50-13.60 (br s, 1H)

Compound (F59)

Major rotamer 70%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40-1.47 (m, 3H) 1.56-1.65 (m, 3H)1.68-1.78 (m, 1H) 1.84-2.01 (m, 1H) 3.24-3.31 (m, 2H) 3.64-3.76 (m, 1H)4.09-4.22 (m, 2H) 5.66-5.78 (m, 1H) 5.90 (t, J=3.03 Hz, 1H) 6.03 (br s,1H) 6.7 (br s, 1H) 7.18 (s, 1H) 7.22-7.29 (m, 1H) 8.16-8.28 (m, 3H)8.29-8.43 (m, 2H) 9.18 (s, 1H) 13.42-13.69 (m, 1H)

Minor rotamer 30%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40-1.47 (m, 3H) 1.48-1.55 (m, 3H)1.84-2.01 (m, 2H) 3.24-3.31 (m, 2H) 4.09-4.22 (m, 2H) 4.33-4.42 (m, 1H)5.21 (m, 1H) 5.70 (br s, 1H) 5.82 (t, J=3.03 Hz, 1H) 6.68 (br s, 1H)7.05 (s, 1H) 7.22-7.29 (m, 1H) 8.16-8.28 (m, 3H) 8.29-8.43 (m, 2H) 9.18(s, 1H) 13.42-13.69 (m, 1H)

Compound (F60)

Major rotamer 65%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39-1.45 (m, 3H) 1.45-1.50 (d, J=6.6Hz, 3H) 2.76-3.04 (m, 2H) 3.25-3.29 (m, 2H) 3.41-3.50 (m, 1H) 4.03 (dd,J=13.6, 5.1 Hz, 1H) 5.54-5.60 (m, 1H) 7.03 (d, J=5.5 Hz, 1H) 7.19-7.28(m, 2H) 7.39 (d, J=5.6 Hz, 1H) 8.17-8.28 (m, 3H) 8.32-8.40 (m, 2H) 9.19(d, J=2.0 Hz, 1H) 13.36-13.60 (br s, 1H)

Minor rotamer 35%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39-1.50 (m, 3H) 1.54 (d, J=6.6 Hz, 3H)1.91 (s, 1H) 2.76-3.04 (m, 2H) 3.25-3.29 (m, 2H) 4.70-4.78 (m, 1H)4.96-5.01 (m, 1H) 6.80 (d, J=5.1 Hz, 1H) 7.19-7.28 (m, 2H) 7.30 (d,J=5.1 Hz, 1H) 8.17-8.28 (m, 3H) 8.32-8.40 (m, 2H) 9.19 (d, J=2.0 Hz, 1H)13.36-13.60 (br s, 1H)

Compound (F61)

Major rotamer 65%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39-1.45 (m, 3H) 1.49-1.55 (m, 3H)3.21-3.27 (m, 2H) 3.62-3.72 (m, 1H) 3.98-3.96 (m, 1H) 4.00 (br d, J=6.1Hz, 1H) 4.09-4.15 (m, 1H) 5.07 (d, J=1.0 Hz, 2H) 5.66-5.71 (m, 1H)5.92-5.94 (m, 1H) 6.04 (t, J=3.0 Hz, 1H) 6.65 (s, 1H) 7.20 (d, J=3.5 Hz,1H) 7.24 (s, 1H), 7.32 (d, J=8.1 Hz, 1H) 7.52 (s, 1H) 7.71 (t, J=6.8 Hz,1H) 13.05 (br s, 1H)

Minor rotamer 35%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39-1.45 (m, 3H) 1.49-1.55 (m, 3H)3.21-3.27 (m, 2H) 3.44-3.54 (m, 1H) 4.00 (br d, J=6.1 Hz, 1H) 4.09-4.15(m, 1H) 4.65-4.69 (m, 1H) 5.07 (d, J=1.0 Hz, 2H) 5.19-5.24 (m, 1H)5.71-5.74 (m, 1H) 6.04 (t, J=3.0 Hz, 1H) 6.65 (s, 1H) 7.20 (d, J=3.5 Hz,1H) 7.24 (s, 1H), 7.32 (d, J=8.1 Hz, 1H) 7.52 (s, 1H) 7.71 (t, J=6.8 Hz,1H) 13.05 (br s, 1H)

Compound (F62)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.01-1.13 (m, 3H) 1.13-1.45 (m, 3H)1.46-1.78 (m, 4H) 1.84 (s, 3H) 1.86-2.03 (m, 1H) 2.87 (t, J=12.6 Hz, 1H)3.60-3.72 (m, 1H) 3.92 (br d, J=13.2 Hz, 1H) 4.60 (d, J=6.3 Hz, 2H) 4.99(s, 2H) 5.02 (d, J=6.6 Hz, 2H) 6.99-7.18 (m, 2H) 7.24 (d, J=8.20 Hz, 1H)7.45 (s, 1H) 7.56 (t, J=7.3 Hz, 1H) 13.03 (br s, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.01-1.13 (m, 3H) 1.13-1.45 (m, 3H)1.46-1.78 (m, 4H) 1.84 (s, 3H) 1.86-2.03 (m, 1H) 3.02-3.15 (m, 1H) 3.47(br d, J=15.1 Hz, 1H) 4.31-4.42 (m, 1H) 4.60 (d, J=6.30Hz, 2H) 4.99 (s,2H) 5.02 (d, J=6.6 Hz, 2H) 6.99-7.18 (m, 2H) 7.24 (d, J=8.2 Hz, 1H) 7.45(s, 1H) 7.56 (t, J=7.3 Hz, 1H) 13.03 (br s, 1H)

Compound (F63)

Major rotamer 65%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39-1.47 (m, 3H) 1.49 (d, J=7.1 Hz, 3H)2.73-3.06 (m, 2H) 3.18-3.30 (m, 2H) 3.46 (br t, J=11.1 Hz, 1H) 3.96-4.09(m, 1H) 5.50-5.62 (m, 1H) 7.03 (d, J=5.6 Hz, 1H) 7.23 (s, 1H) 7.25-7.29(m, 1H) 7.39 (d, J=5.6 Hz, 1H) 8.14-8.30 (m, 3H) 8.30-8.42 (m, 2H) 9.19(d, J=2.0 Hz, 1H) 13.49 (br s, 1H)

Minor rotamer 35%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39-1.47 (m, 3H) 1.54 (d, J=6.6 Hz, 3H)2.73-3.06 (m, 2H) 3.18-3.30 (m, 2H) 3.96-4.09 (m, 1H) 4.73 (br d, J=11.6Hz, 1H) 4.94-5.04 (m, 1H) 6.80 (d, J=5.6 Hz, 1H) 7.19 (s, 1H) 7.25-7.29(m, 1H) 7.30 (d, J=5.1 Hz, 1H) 8.14-8.30 (m, 3H) 8.30-8.42 (m, 2H) 9.19(d, J=2.0 Hz, 1H) 13.49 (br s, 1H)

Compound (F66)

Major rotamer 65%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37-1.46 (m, 3H) 1.49 (d, J=6.6 Hz, 1H)2.73-3.04 (m, 2H) 3.19-3.30 (m, 2H) 3.40-3.51 (m, 1H) 4.03 (br dd,J=14.0, 4.9 Hz, 1H) 5.08 (s, 2H) 5.50-5.62 (m, 1H) 7.04 (d, J=5.0 Hz,1H) 7.16-7.25 (m, 2H) 7.34 (d, J=8.2 Hz, 1H) 7.40 (d, J=5.0 Hz, 1H) 7.54(s, 1H) 7.64-7.79 (m, 1H) 12.71-13.25 (m, 1H)

Minor rotamer 35%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37-1.46 (m, 3H) 1.54 (d, J=6.6 Hz, 1H)2.73-3.04 (m, 2H) 3.19-3.30 (m, 3H) 4.73 (br dd, J=12.5, 3.9 Hz, 1H)4.94-5.02 (m, 1H) 5.08 (s, 2H) 6.81 (d, J=5.4 Hz, 1H) 7.16-7.25 (m, 2H)7.31 (d, J=5.0 Hz, 1H) 7.34 (d, J=8.2 Hz, 1H) 7.54 (s, 1H) 7.64-7.79 (m,1H) 12.71-13.25 (m, 1H)

Compound (F67)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17-1.29 (m, 2H) 1.48 (d, J=6.6 Hz, 3H)1.60-1.67 (m, 3H) 2.55-3.03 (m, 3H) 3.16-3.24 (m, 1H) 3.37-3.48 (m, 1H)4.03 (br dd, J=14.2, 5.1 Hz, 1H) 5.08 (s, 2H) 5.52-5.58 (m, 1H) 7.02 (d,J=5.6 Hz, 1H) 7.12-7.21 (m, 2H) 7.28-7.39 (m, 2H) 7.53 (s, 1H) 7.73 (brt, J=7.3 Hz, 1H) 12.93-13.06 (m, 1H)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17-1.29 (m, 2H) 1.53 (d, J=6.6 Hz, 3H)1.60-1.67 (m, 3H) 2.55-3.03 (m, 3H) 3.16-3.24 (m, 1H) 3.33 (br s, 1H)4.69-4.75 (m, 1H) 4.99 (br d, J=6.6 Hz, 1H) 5.08 (s, 2H) 6.80 (d, J=5.1Hz, 1H) 7.12-7.21 (m, 2H) 7.28-7.39 (m, 2H) 7.53 (s, 1H) 7.73 (br t,J=7.3 Hz, 1H) 12.93-13.06 (m, 1H)

Compound (F68)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17-1.29 (m, 2H) 1.48 (d, J=6.6 Hz, 3H)1.60-1.67 (m, 3H) 2.55-3.03 (m, 3H) 3.16-3.24 (m, 1H) 3.37-3.48 (m, 1H)4.03 (br dd, J=14.2, 5.1 Hz, 1H) 5.08 (s, 2H) 5.52-5.58 (m, 1H) 7.02 (d,J=5.6 Hz, 1H) 7.12-7.21 (m, 2H) 7.28-7.39 (m, 2H) 7.53 (s, 1H) 7.73 (brt, J=7.3 Hz, 1H) 12.93-13.06 (m, 1H)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17-1.29 (m, 2H) 1.53 (d, J=6.6 Hz, 3H)1.60-1.67 (m, 3H) 2.55-3.03 (m, 3H) 3.16-3.24 (m, 1H) 3.33 (br s, 1H)4.69-4.75 (m, 1H) 4.99 (br d, J=6.6 Hz, 1H) 5.08 (s, 2H) 6.80 (d, J=5.1Hz, 1H) 7.12-7.21 (m, 2H) 7.28-7.39 (m, 2H) 7.53 (s, 1H) 7.73 (br t,J=7.3 Hz, 1H) 12.93-13.06 (m, 1H)

Compound (M29)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.67 (br s, 1H) 8.19 (t, J=6.8 Hz, 1H)7.96 (t, J=6.8 Hz, 1H) 7.78 (d, J=16.1 Hz, 1H) 7.43 (t, J=7.9 Hz, 1H)7.18 (d, J=3.5 Hz, 1H) 7.12 (s, 1H) 6.70 (d, J=16.1 Hz, 1H) 4.00 (br d,J=13.2 Hz, 1H) 3.63-3.73 (m, 1H) 3.04-3.21 (m, 2H) 2.90-2.98 (m, 1H)2.40-2.47 (m, 1H) 1.89-1.99 (m, 1H) 1.21-1.87 (m, 7H) 1.11 (d, J=6.3 Hz,3H) 0.96-1.01 (m, 6H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.67 (br s, 1H) 8.19 (t, J=6.8 Hz, 1H)7.96 (t, J=6.8 Hz, 1H) 7.78 (d, J=16.1 Hz, 1H) 7.43 (t, J=7.9 Hz, 1H)7.19 (d, J=3.5 Hz, 1H) 7.15 (s, 1H) 6.70 (d, J=16.1 Hz, 1H) 4.39-4.50(m, 1H) 3.53 (br d, J=15.4 Hz, 1H) 3.04-3.21 (m, 3H) 2.40-2.47 (m, 1H)2.03-2.09 (m, 1H) 1.21-1.87 (m, 7H) 1.15 (d, J=6.3 Hz, 3H) 0.96-1.01 (m,6H)

Compound (M30)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.60 (br s, 1H) 9.23 (s, 1H) 8.73-8.81(m, 1H) 8.44 (t, J=7.9 Hz, 1H) 7.85 (br d, J=12.3 Hz, 1H) 7.61-7.78 (m,3H) 7.21 (d, 3.3 Hz, 1H) 6.72 (d, J=16.1 Hz, 1H) 4.06 (s, 3H) 3.97-4.14(m, 1H) 3.68-3.76 (m, 1H, 2.95 (br t, J=12.5 Hz, 1H) 1.89-2.01 (m, 1H)1.22-1.86 (m, 7H) 1.14 (br d, J=6.3 Hz, 3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.60 (br s, 1H) 9.23 (s, 1H) 8.73-8.81(m, 1H) 8.44 (t, J=7.9 Hz, 1H) 7.85 (br d, J=12.3 Hz, 1H) 7.61-7.78 (m,3H) 7.22 (d, 3.3 Hz, 1H) 6.72 (d, J=16.1 Hz, 1H) 4.42-4.52 (m, 1H) 4.06(s, 3H) 3.56 (br d, J=15.1 Hz, 1H) 3.09-3.19 (m, 1H) 2.03-2.12 (m, 1H)1.22-1.86 (m, 7H) 1.18 (br d, J=6.3 Hz, 3H)

Compound (M31)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09-1.20 (m, 3H) 1.22-1.37 (m, 3H) 1.42(t, J=7.5 Hz, 3H) 1.53-1.86 (m, 4H) 1.87-2.12 (m, 1H) 2.93 (t, J=12.1Hz, 1H) 3.22-3.28 (m, 2H) 3.67-3.74 (m, 1H) 3.97-4.04 (m, 1H) 6.19 (d,J=12.1 Hz, 1H) 7.07-7.13 (m, 3H) 7.34 (t, J=7.8 Hz, 1H) 7.58 (t, J=6.8Hz, 1H) 8.10 (t, J=7.5 Hz, 1H) 12.55 (br s, 1H)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09-1.20 (m, 3H) 1.22-1.37 (m, 3H) 1.42(t, J=7.5 Hz, 3H) 1.53-1.86 (m, 4H) 1.87-2.12 (m, 1H) 3.07-3.18 (m, 1H)3.22-3.28 (m, 2H) 3.50-3.58 (m, 1H) 4.41-4.48 (m, 1H) 6.19 (d, J=12.1Hz, 1H) 7.07-7.13 (m, 3H) 7.34 (t, J=7.8 Hz, 1H) 7.58 (t, J=6.8 Hz, 1H)8.10 (t, J=7.5 Hz, 1H) 12.55 (br s, 1H)

Compound (M32)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.13 (d, J=6.6 Hz, 3H) 1.25-1.38 (m, 3H)1.42 (t, J=7.1 Hz, 3H) 1.55-1.83 (m, 4H) 1.91-1.99 (m, 1H) 2.85-3.00 (m,1H) 3.26 (q, J=7.6 Hz, 2H) 3.67-3.74 (m, 1H) 3.98 (d, J=1.0 Hz, 3H)4.00-4.05 (m, 1H) 6.67 (d, J=16.2 Hz, 1H) 7.10-7.13 (m, 1H) 7.16-7.21(m, 1H) 7.73-7.80 (m, 2H) 7.86-7.94 (m, 1H) 12.58 (br s, 1H)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.6 Hz, 3H) 1.25-1.38 (m, 3H)1.42 (t, J=7.1 Hz, 3H) 1.55-1.83 (m, 4H) 2.02-2.08 (m, 1H) 3.07-3.17 (m,1H) 3.26 (q, J=7.6 Hz, 2H) 3.51-3.57 (m, 1H) 3.98 (d, J=1.0 Hz, 3H)4.42-4.46 (m, 1H) 6.67 (d, J=16.2 Hz, 1H) 7.10-7.13 (m, 1H) 7.16-7.21(m, 1H) 7.73-7.80 (m, 2H) 7.86-7.94 (m, 1H) 12.58 (br s, 1H)

Compound (M33)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (d, J=6.3 Hz, 3H) 1.22-1.50 (m, 3H)1.59-1.66 (m, 4H) 1.93 (, 3H) 1.90-2.1 (m, 1H) 2.95 (br t, J=12.5 Hz,1H) 3.66-3.78 (m, 1H) 4.00 (br d, J=13.2 Hz, 1H) 4.69 (d, J=6.6 Hz, 2H)5.10 (d, J=6.3 Hz, 2H) 6.66 (d, J=16.1 Hz, 1H) 7.15 (s, 1H) 7.20 (dd,J=3.2, 7.9 Hz, 1H) 7.39 (t, J=7.9 Hz, 1H) 7.64 (br d, J=16.4 Hz, 1H)7.89 (br t, J=7.1 Hz, 1H) 8.08 (br t, J=6.9 Hz, 1H) 12.0-13.0 (m, 1H)

Minor rotamers 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 (d, J=6.3 Hz, 3H) 1.22-1.50 (m, 3H)1.59-1.66 (m, 4H) 1.90-2.1 (m, 1H) 1.93 (s, 3H) 3.11-3.18 (m,1H3.49-3.63 (m, 1H) 4.39-4.50 (m, 1H) 4.69 (d, J=6.6 Hz, 2H) 5.10 (d,J=6.3 Hz, 2H) 6.66 (d, J=16.1 Hz, 1H) 7.15 (s, 1H) 7.20 (dd, J=3.2, 7.9Hz, 1H) 7.39 (t, J=7.9 Hz, 1H) 7.64 (br d, J=16.4 Hz, 1H) 7.89 (br t,J=7.1 Hz, 1H) 8.08 (br t, J=6.9 Hz, 1H) 12.0-13.0 (m, 1H)

Compound (M34)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.13 (d, J=6.6 Hz, 3H) 1.20-1.33 (m, 2H)1.42 (t, J=7.6 Hz, 3H) 1.57-1.80 (m, 4H) 1.85-2.09 (m, 1H) 2.92 (t,J=12.4 Hz, 1H) 3.06-3.19 (m, 1H) 3.21-3.26 (m, 2H) 3.65-3.81 (m, 1H)3.95-4.06 (m, 4H) 6.72 (d, J=16.2 Hz, 1H) 7.04-7.11 (m, 2H) 7.16 (d,J=8.6 Hz, 1H) 7.80 (d, J=16.7 Hz, 1H) 8.16 (t, J=8.6 Hz, 1H) 12.49 (brs, 1H)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (d, J=6.6 Hz, 3H) 1.20-1.33 (m, 2H)1.42 (t, J=7.6 Hz, 3H) 1.57-1.83 (m, 4H) 1.85-2.09 (m, 2H) 3.06-3.19 (m,1H) 3.21-3.26 (m, 2H) 3.55 (m, 1H) 3.99 (s, 3H) 4.40-4.50 (m, 1H) 6.72(d, J=16.2 Hz, 1H) 7.04-7.11 (m, 2H) 7.16 (d, J=8.6 Hz, 1H) 7.80 (d,J=16.7 Hz, 1H) 8.16 (t, J=8.6 Hz, 1H) 12.49 (br s, 1H

Compound (M35)

Major rotamer 53%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.26 (d, J=6.8 Hz, 3H) 1.36-1.51 (m, 4H)1.62-1.81 (m, 3H) 1.96 (br d, J=16.7 Hz, 1H) 2.20-2.44 (m, 3H) 3.17-3.30(m, 3H) 3.49-3.56 (m, 1H) 4.38 (br d, J=14.2 Hz, 1H) 5.54 (br d, J=18.3Hz, 1H) 5.67 (br s, 1H) 6.70 (d, J=15.8 Hz, 1H) 7.10 (d, J=4.7 Hz, 1H)7.15-7.21 (dd, J=3.5 Hz, 24.9 Hz, 1H) 7.64 (d, J=16.1 Hz, 1H) 7.71 (d,J=8.2 Hz, 1H) 7.81 (d, J=12.3 Hz, 1H) 8.20 (td, J=7.9, 1.9 Hz, 1H) 12.57(br s, 1H)

Minor rotamer 47%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.28 (d, J=6.8 Hz, 3H) 1.36-1.51 (m, 4H)1.62-1.81 (m, 3H) 2.12 (d, J=16.4 Hz, 1H) 2.20-2.44 (m, 3H) 2.89-2.97(m, 1H) 3.17-3.30 (m, 2H) 3.63 (q, J=6.5 Hz, 1H) 4.62 (q, J=6.9 Hz, 1H)5.54 (br d, J=18.3 Hz, 1H) 5.67 (br s, 1H) 6.70 (d, J=15.8 Hz, 1H) 7.10(d, J=4.7 Hz, 1H) 7.15-7.21 (dd, J=3.5 Hz, 24.9 Hz, 1H) 7.64 (d, J=16.1Hz, 1H) 7.71 (d, J=8.2 Hz, 1H) 7.81 (d, J=12.3 Hz, 1H) 8.20 (td, J=7.9,1.9 Hz, 1H) 12.57 (br s, 1H)

Compound (M44)

Major rotamer (65%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.58 (br s, 1H) 8.22 (t, J=8.0 Hz, 1H)7.82 (dd, J=12.3, 0.9 Hz, 1H) 7.71 (dd, J=8.4, 1.4 Hz, 1H) 7.64 (d,J=15.8 Hz, 1H) 7.20-7.28 (m, 2H) 6.71 (d, J=16.1 Hz, 1H) 6.64-6.68 (m,1H) 6.05 (t, J=3.2 Hz, 1H) 5.94 (d, J=3.2 Hz, 1H) 5.69 (q, J=6.7 Hz, 1H)4.07-4.18 (m, 1H) 3.97-4.06 (m, 1H) 3.62-3.74 (m, 1H) 3.22-3.31 (m, 3H)1.50 (d, J=6.6 Hz, 3H) 1.40-1.47 (m, 3H)

Minor rotamer (35%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.58 (br s, 1H) 8.22 (t, J=8.0 Hz, 1H)7.82 (dd, J=12.3, 0.9 Hz, 1H) 7.71 (dd, J=8.4, 1.4 Hz, 1H) 7.64 (d,J=15.8 Hz, 1H) 7.20-7.28 (m, 2H) 6.71 (d, J=16.1 Hz, 1H) 6.64-6.68 (m,1H) 5.99 (t, J=3.2 Hz, 1H) 5.73 (br s, 1H) 5.21 (q, J=6.6 Hz, 1H)4.64-4.71 (m, 1H) 4.07-4.18 (m, 1H) 3.93 (td, J=12.1, 3.9 Hz, 1H)3.45-3.54 (m, 1H) 3.22-3.31 (m, 2H) 1.54 (d, J=6.6 Hz, 3H) 1.40-1.47 (m,3H)

Compound (M45)

Major rotamer 65%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40-1.45 (m, 3H) 1.49-1.55 (m, 3H)3.24-3.26 (m, 2H) 3.64-3.72 (m, 1H) 3.90-3.97 (m, 1H) 3.98-4.01 (m, 1H)4.09-4.15 (m, 1H) 5.68-5.74 (m, 1H) 5.94 (br s, 1H) 5.99-6.05 (m, 1H)6.67 (d, J=8.6 Hz, 1H) 6.72 (s, 1H) 7.21-7.25 (m, 2H) 7.43 (t, J=7.8 Hz,1H) 7.79 (d, J=16.2 Hz, 1H) 7.96 (br t, J=7.1 Hz, 1H) 8.21 (br t, J=7.6Hz, 1H) 12.6 (br s, 1H)

Minor rotamer 35%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40-1.45 (m, 3H) 1.49-1.55 (m, 3H)3.24-3.27 (m, 2H) 3.44-3.53 (m, 1H) 3.90-3.97 (m, 1H) 3.98-4.01 (m, 1H)4.09-4.15 (m, 1H) 4.65-4.71 (m, 1H) 5.22 (br d, J=7.1 Hz, 1H) 5.94 (brs, 1H) 6.67 (d, J=8.6 Hz, 1H) 6.72 (s, 1H) 7.21-7.25 (m, 2H) 7.43 (t,J=7.8 Hz, 1H) 7.79 (d, J=16.2 Hz, 1H) 7.96 (br t, J=7.1 Hz, 1H) 8.21 (brt, J=7.6 Hz, 1H) 12.6 (br s, 1H)

Compound (M46)

Major rotamer 65%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.27-1.37 (m, 4H) 1.47 (d, J=6.9 Hz, 3H)2.74-3.00 (m, 3H) 3.37-3.48 (m, 1H) 3.94 (br dd, J=13.6, 4.7 Hz, 1H)5.55 (q, J=6.5 Hz, 1H) 6.71 (d, J=16.1 Hz, 1H) 6.91-6.96 (m, 1H) 7.03(d, J=5.4 Hz, 1H) 7.22 (s, 1H) 7.39 (d, J=5.0 Hz, 1H) 7.44 (t, J=7.6 Hz,1H) 7.80 (d, J=16.08 Hz, 1H) 7.97 (br t, J=7.1 Hz, 1H) 8.21-8.27 (m, 1H)12.68 (br s, 1H)

minor rotamer 35%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.27-1.37 (m, 4H) 1.51 (d, J=6.9 Hz, 3H)2.74-3.00 (m, 3H) 3.20-3.25 (m, 1H) 4.72 (br dd, J=13.1, 5.2 Hz, 1H)4.91 (q, J=6.3 Hz, 1H) 6.71 (d, J=16.1 Hz, 1H) 6.80 (d, J=5.4 Hz, 1H)6.91-6.96 (m, 1H) 7.22 (m, 1H) 7.30 (d, J=5.0 Hz, 1H) 7.44 (t, J=7.57Hz, 1H) 7.80 (d, J=16.1 Hz, 1H) 7.97 (br t, J=7.1 Hz, 1H) 8.21-8.27 (m,1H) 12.68 (br s, 1H)

Compound (M47)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.95-1.02 (m, 2H) 1.18-1.30 (m, 2H) 1.47(d, J=6.6 Hz, 3H) 1.65 (s, 3H) 2.74-2.84 (m, 1H) 2.85-3.03 (m, 1H)3.34-3.48 (m, 1H) 4.02 (br dd, J=13.1, 4.6 Hz, 1H) 5.52-5.59 (m, 1H)6.70 (d, J=16.2 Hz, 1H) 7.02 (d, J=5.1 Hz, 1H) 7.12-7.18 (m, 1H) 7.23(d, J=3.5 Hz, 1H) 7.38 (d, J=5.1 Hz, 1H) 7.45 (t, J=7.6 Hz, 1H) 7.80 (d,J=16.2 Hz, 1H) 7.96 (t, J=7.1 Hz, 1H) 8.23 (br t, J=7.3 Hz, 1H) 12.60(br s, 1H)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.95-1.02 (m, 2H) 1.18-1.30 (m, 2H) 1.53(d, J=6.6 Hz, 3H) 1.64 (s, 3H) 2.85-3.03 (m, 2H) 3.14-3.25 (m, 1H)4.68-4.76 (m, 1H) 4.99 (br d, J=7.1 Hz, 1H) 6.70 (d, J=16.2 Hz, 1H) 6.80(d, J=5.1 Hz, 1H) 7.12-7.18 (m, 1H) 7.23 (d, J=3.5 Hz, 1H) 7.29 (d,J=5.1 Hz, 1H) 7.45 (t, J=7.6 Hz, 1H) 7.80 (d, J=16.2 Hz, 1H) 7.96 (t,J=7.1 Hz, 1H) 8.23 (br t, J=7.3 Hz, 1H) 12.60 (br s, 1H)

Compound (M48)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39-1.47 (m, 3H) 1.48 (d, J=6.6 Hz, 3H)2.73-2.84 (m, 1H) 2.84-3.07 (m, 1H) 3.27 (q, J=7.6 Hz, 2H) 3.36-3.53 (m,1H) 4.02 (br dd, J=13.9, 4.8 Hz, 1H) 5.57 (q, J=6.6 Hz, 1H) 6.70 (d,J=15.7 Hz, 1H) 7.03 (d, J=5.1 Hz, 1H) 7.17-7.25 (m, 2H) 7.38 (d, J=5.1Hz, 1H) 7.43 (t, J=8.1 Hz, 1H) 7.79 (d, J=16.2 Hz, 1H) 7.96 (t, J=6.6Hz, 1H) 8.21 (t, J=6.6 Hz, 1H) 12.63 (br s, 1H)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39-1.47 (m, 3H) 1.53 (d, J=6.6 Hz, 3H)2.84-3.07 (m, 2H) 3.22-3.30 (m, 3H) 4.70-4.77 (m, 1H) 4.94-5.05 (m, 1H)6.70 (d, J=15.7 Hz, 1H) 6.80 (d, J=5.6 Hz, 1H) 7.17-7.25 (m, 2H) 7.30(d, J=5.6 Hz, 1H) 7.43 (t, J=8.1 Hz, 1H) 7.79 (d, J=16.2 Hz, 1H) 7.96(t, J=6.6 Hz, 1H) 8.21 (t, J=6.6 Hz, 1H) 12.63 (br s, 1H)

Compound (M49)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39-1.47 (m, 3H) 1.48 (d, J=6.6 Hz, 3H)2.73-2.84 (m, 1H) 2.84-3.07 (m, 1H) 3.27 (q, J=7.6 Hz, 2H) 3.36-3.53 (m,1H) 4.02 (br dd, J=13.9, 4.8 Hz, 1H) 5.57 (q, J=6.6 Hz, 1H) 6.70 (d,J=15.7 Hz, 1H) 7.03 (d, J=5.1 Hz, 1H) 7.17-7.25 (m, 2H) 7.38 (d, J=5.1Hz, 1H) 7.43 (t, J=8.1 Hz, 1H) 7.79 (d, J=16.2 Hz, 1H) 7.96 (t, J=6.6Hz, 1H) 8.21 (t, J=6.6 Hz, 1H) 12.63 (br s, 1H)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39-1.47 (m, 3H) 1.53 (d, J=6.6 Hz, 3H)2.84-3.07 (m, 2H) 3.22-3.30 (m, 3H) 4.70-4.77 (m, 1H) 4.94-5.05 (m, 1H)6.70 (d, J=15.7 Hz, 1H) 6.80 (d, J=5.6 Hz, 1H) 7.17-7.25 (m, 2H) 7.30(d, J=5.6 Hz, 1H) 7.43 (t, J=8.1 Hz, 1H) 7.79 (d, J=16.2 Hz, 1H) 7.96(t, J=6.6 Hz, 1H) 8.21 (t, J=6.6 Hz, 1H) 12.63 (br s, 1H)

Compound (M51)

Major rotamer 70%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.30 (d, J=6.6 Hz, 3H) 1.43 (t, J=7.4Hz, 3H) 1.48-1.66 (m, 4H) 1.77-2.01 (m, 4H) 2.08-2.33 (m, 2H) 3.24-3.30(m, 1H) 3.26 (q, J=7.6 Hz, 2H) 3.72 (br dd, J=13.1, 5.5 Hz, 1H) 4.62 (brd, J=6.3 Hz, 1H) 6.71 (d, J=16.1 Hz, 1H) 7.13-7.18 (m, 1H) 7.22 (d,J=2.8 Hz, 1H) 7.43 (t, J=7.7 Hz, 1H) 7.79 (d, J=16.1 Hz, 1H) 7.97 (br t,J=7.3 Hz, 1H) 8.22 (br t, J=7.3 Hz, 1H) 12.68 (br s, 1H)

Minor rotamer 30%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.6 Hz, 3H) 1.43 (t, J=7.41Hz, 3H) 1.48-1.66 (m, 4H) 1.77-2.01 (m, 4H) 2.08-2.33 (m, 2H) 3.02-3.09(m, 1H) 3.26 (q, J=7.6 Hz, 2H) 3.99-4.06 (m, 1H) 4.47 (br dd, J=13.1,6.2 Hz, 1H) 6.71 (d, J=16.1 Hz, 1H) 7.13-7.18 (m, 1H) 7.22 (d, J=2.8 Hz,1H) 7.43 (t, J=7.7 Hz, 1H) 7.79 (d, J=16.1 Hz, 1H) 7.97 (br t, J=7.3 Hz,1H) 8.22 (br t, J=7.3 Hz, 1H) 12.68 (br s, 1H)

Compound (O5)

Major rotamer (60%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21-1.38 (m, 5H) 1.43-1.56 (m, 5H)1.92-2.02 (m, 1H) 2.66-2.74 (m, 1H) 2.85-3.05 (m, 2H) 3.34-3.50 (m, 1H)3.76-3.84 (m, 1H) 5.59 (q, J=6.9 Hz, 1H) 6.85-6.92 (m, 1H) 7.06-7.26 (m,6H) 7.32 (d, J=7.6 Hz, 1H) 8.09 (t, J=7.9 Hz, 1H) 12.27-12.48 (m, 1H)

Minor rotamer (40%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21-1.38 (m, 5H) 1.43-1.56 (m, 5H)1.92-2.02 (m, 1H) 2.42-2.44 (m, 1H) 2.85-3.05 (m, 2H) 3.22-3.25 (m, 1H)4.52-4.58 (m, 1H) 4.96 (d, J=6.6 Hz, 1H) 6.85-6.92 (m, 1H) 7.06-7.26 (m,7H) 8.09 (t, J=7.9 Hz, 1H) 12.27-12.48 (m, 1H)

Compound (O7)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.10 (d, J=6.3 Hz, 3H) 1.20-1.40 (m, 7H)1.42-1.56 (m, 3H) 1.59-1.82 (m, 3H) 1.89-1.98 (m, 2H) 2.43-2.55 (m, 1H)2.87-2.97 (m, 2H) 3.57-3.67 (m, 1H) 3.98 (br d, J=13.6 Hz, 1H) 6.82 (d,J=2.2 Hz, 1H) 7.06 (dd, J=7.9, 3.5 Hz, 1H) 7.20 (dd, J=8.2, 1.6 Hz, 1H)7.24 (dd, J=12.9, 1.6 Hz, 1H) 8.08 (t, J=8.0 Hz, 1H) 12.41 (br s, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (d, J=6.3 Hz, 3H) 1.20-1.40 (m, 7H)1.42-1.56 (m, 3H) 1.59-1.82 (m, 3H) 1.89-1.98 (m, 2H) 1.98-2.08 (m, 1H)2.43-2.55 (m, 1H) 2.87-2.97 (m, 1H) 3.06-3.26 (m, 1H) 3.43-3.51 (br d,J=15.4 Hz, 1H) 4.42 (dt, J=11.9, 6.2 Hz, 1H) 6.82 (d, J=2.2 Hz, 1H) 7.06(dd, 3.5 Hz, 1H) 7.20 (dd, J=8.2, 1.6 Hz, 1H) 7.24 (dd, J=12.9, 1.6 Hz,8.08 (t, J=8.0 Hz, 1H) 12.41 (br s, 1H)

Compound (O17)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (t, J=5.7 Hz, 3H) 1.17-1.85 (m,9H)1.91 (s, 3H) 1.92-2.11 (m, 2H) 2.94 (br t, J=12.6 Hz, 1H) 3.10-3.29(m, 1H) 3.68-3.76 (m, 1H) 3.99 (br d, J=13.2 Hz, 1H) 4.43 (m 1H) 4.67(d, J=6.3 Hz, 2H) 5.09 (br d, J=6.6 Hz, 2H) 7.09 (br dd, J=7.4 Hz, 3.5Hz, 1H) 7.12 (s, 1H) 7.19 (br d, J=8.2 Hz, 1H) 7.23 (br d, J=12.6 Hz,1H) 7.98 (t, J=8.0 Hz, 1H) 12.46 (s, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (t, J=5.7 Hz, 3H) 1.17-1.85 (m,9H)1.91 (s, 3H) 1.92-2.11 (m, 2H) 3.10-3.17 (m, 1H) 3.54 (br d, J=6.3Hz, 1H3.99 (br d, J=13.2 Hz, 1H) 4.43 (m 1H) 4.67 (br d, J=6.3 Hz, 2H)5.09 (br d, J=6.6 Hz, 2H) 7.09 (br dd, J=7.4 Hz, 3.5 Hz, 1H) 7.12 (s,1H) 7.19 (br d, J=8.2 Hz, 1H) 7.23 (br d, J=12.6 Hz, 1H) 7.98 (t, J=8.0Hz, 1H) 12.46 (s, 1H)

Compound (O18)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (d, J=6.6 Hz, 3H) 1.22-1.38 (m, 4H)1.42 (t, J=7.6 Hz, 1H) 1.52-1.85 (m, 5H) 2.45-2.50 (m, 1H) 2.90-2.09 (m,1H) 2.93 (br t, J=12.6 Hz, 1H) 3.20-3.30 (dd, J=14.5, 7.3 Hz, 1H)3.36-3.46 (m, 1H) 3.61-3.67 (m, 1H) 3.67-3.74 (m, 1H) 4.00 (br d, J=13.6Hz, 1H) 7.09-7.15 (m, 2H) 7.40 (br d, J=8.2 Hz, 1H) 7.48 (br d, J=12.6Hz, 1H) 8.14 (t, J=8.2 Hz, 1H) 13.37 (s, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (d, J=6.6 Hz, 3H) 1.22-1.38 (m, 4H)1.42 (t, J=7.6 Hz, 1H) 1.52-1.85 (m, 5H) 2.45-2.50 (m, 1H) 2.90-2.09 (m,1H) 3.10-3.19 (m, 1H) 3.20-3.30 (dd, J=14.5, 7.3 Hz, 1H) 3.36-3.46 (m,1H) 3.49-3.57 (m, 1H) 3.61-3.67 (m, 1H) 4.41-4.47 (m, 1H) 7.09-7.15 (m,2H) 7.40 (br d, J=8.2 Hz, 1H) 7.48 (br d, J=12.6 Hz, 1H) 8.14 (t, J=8.2Hz, 1H) 13.30-13.43 (m, 1H)

Compound (O19)

Major rotamer 67%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.39-1.56 (m, 8H) 1.91-2.03 (m, 1H)3.22-3.31 (m, 2H) 3.62-3.72 (m, 1H) 3.90-4.04 (m, 2H) 4.07-4.17 (m, 1H)4.65-4.71 (m, 1H) 5.66-5.74 (m, 1H) 5.95 (m, 1H), 6.05 (t, J=3.0 Hz, 1H)6.66 (s, 1H) 7.15 (d, J=3.5 Hz, 1H) 7.19-7.27 (m, 3H) 8.08 (t, J=8.0 Hz,1H) 12.44 (br s, 1H)

Minor rotamer 33%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.39-1.56 (m, 8H) 1.91-2.03 (m, 1H)3.22-3.31 (m, 2H) 3.42-3.52 (m, 1H) 3.90-4.04 (m, 2H) 4.07-4.17 (m, 1H)4.70 (m, 1H), 5.18-5.23 (m, 1H) 5.73 (m, 1H, 5.99 (t, J=3.0 Hz, 1H) 6.66(s, 1H) 7.15 (d, J=3.5 Hz, 1H) 7.19-7.27 (m, 3H) 8.08 (t, J=8.0 Hz, 1H)12.44 (br s, 1H)

Compound (O20)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21-1.39 (m, 5H) 1.42-1.53 (m, 5H)1.91-1.99 (m, 1H) 2.70-2.80 (m, 1H) 2.83-3.01 (m, 2H) 3.36-3.45 (m, 1H)3.92 (br dd, J=13.4, 4.8 Hz, 1H) 5.54 (q, J=7.1 Hz, 1H) 6.87-6.90 (m,1H) 7.02 (d, J=5.6 Hz, 1H) 7.08-7.12 (m, 1H) 7.18-7.27 (m, 2H) 7.38 (d,J=5.6 Hz, 1H) 8.09 (td, J=8.1, 2.5 Hz, 1H) 12.40 (s, 1H)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21-1.39 (m, 5H) 1.42-1.53 (m, 5H)1.91-1.99 (m, 1H) 2.83-3.01 (m, 3H) 3.17-3.29 (m, 1H) 4.68-4.73 (m, 1H)4.90 (q, J=7.1 Hz, 1H) 6.79 (d, J=5.1 Hz, 1H) 6.87-6.90 (m, 1H)7.08-7.12 (m, 1H) 7.18-7.27 (m, 2H) 7.29 (d, J=5.6 Hz, 1H) 8.09 (td,J=8.1, 2.5 Hz, 1H) 12.40 (s, 1H)

Compound (O21)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.93-1.01 (m, 2H) 1.15-1.30 (m, 3H)1.43-1.55 (m, 5H) 1.60-1.66 (m, 3H) 1.93-2.01 (m, 1H) 2.71-2.82 (m, 1H)2.84-3.02 (m, 1H) 3.34-3.46 (m, 1H) 3.96-4.04 (m, 1H) 5.51-5.58 (m, 1H)7.02 (d, J=5.6 Hz, 1H) 7.10-7.15 (m, 2H) 7.20-7.27 (m, 2H) 7.38 (d,J=5.1 Hz, 1H) 8.08 (t, J=7.9 Hz, 1H) 12.41 (s, 1H)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.93-1.01 (m, 2H) 1.15-1.30 (m, 2H)1.43-1.55 (m, 6H) 1.60-1.66 (m, 3H) 1.93-2.01 (m, 1H) 2.84-3.02 (m, 2H)3.19-3.30 (m, 1H) 4.68-4.74 (m, 1H) 4.94-5.01 (m, 1H) 6.79 (d, J=5.6 Hz,1H) 7.10-7.15 (m, 2H) 7.20-7.27 (m, 2H) 7.29 (d, J=5.1 Hz, 1H) 8.08 (t,J=7.9 Hz, 1H) 12.41 (s, 1H)

Compound (O22)

Major rotamer 62%

¹H NMR (400 MHz, DMSO-d₆) 6 1.38-1.54 (m, 9H) 1.93-1.98 (m, 1H)2.74-2.82 (m, 1H) 2.84-3.03 (m, 1H) 3.20-3.30 (m, 2H) 3.38-3.49 (m, 1H)4.01 (dd, J=14.4, 5.3 Hz, 1H) 5.53-5.59 (m, 1H) 7.03 (d, J=5.6 Hz, 1H)7.12-7.30 (m, 4H) 7.39 (d, J=5.1 Hz, 1H) 8.07 (t, J=7.9 Hz, 1H)12.30-12.50 (br s, 1H)

Minor rotamer 38%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.38-1.54 (m, 9H) 1.93-1.98 (m,1H2.84-3.03 (m, 2H) 3.20-3.30 (m, 3H) 4.69-4.76 (m, 1H) 4.97 (q, J=6.6Hz, 1H) 6.79 (d, J=5.1 Hz, 1H) 7.12-7.30 (m, 4H) 7.29 (d, J=5.1 Hz, 1H)8.07 (t, J=7.9 Hz, 1H) 12.30-12.50 (br s, 1H)

Compound (O23)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (d, 6.3 Hz, 3H) 1.22-1.38 (m, 3H)1.43-1.52 (m, 2H) 1.56-1.82 (m, 5H) 1.89-2.10 (m, 2H) 2.94 (br t, J=12.6Hz, 1H) 3.10-3.24 (m, 4H) 3.65-3.72 (m, 1H) 4.00 (br d, J=12.9 Hz, 1H)4.10 (quin, J=8.8 Hz, 1H) 7.12 (dd, J=8.2, 3.2 Hz, 1H) 7.19-7.25 (m, 2H)7.28 (s, 1H), 8.09 (t, J=8.0 Hz, 1H) 12.43 (br s, 1H)

minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 (d, 6.3 Hz, 3H) 1.22-1.38 (m, 3H)1.43-1.52 (m, 3H) 1.56-1.82 (m, 4H) 1.89-2.00 (m, 2H) 3.10-3.24 (m, 5H)3.52 (br d, J=15.1 Hz, 1H) 4.10 (quin, J=8.8 Hz, 1H) 4.45 (dt, J=11.7,5.8 Hz, 1H) 7.12 (dd, 3.2 Hz, 1H) 7.19-7.25 (m, 2H) 7.28 (s, 1H), 8.09(t, J=8.0 Hz, 1H) 12.43 (br s, 1H)

Compound (O24)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.87 (s, 3H) 1.09-1.17 (m, 3H) 1.32 (s,3H) 1.26-1.36 (m, 2H) 1.38-1.51 (m, 1H) 1.41 (t, J=7.3 Hz, 3H) 1.53-1.86(m, 4H) 1.93 (br d, J=5.1 Hz, 1H) 1.96-2.12 (m, 1H) 2.38 (br d, J=5.6Hz, 1H) 2.92 (br t, J=12.9 Hz, 1H) 3.19-3.28 (m, 2H) 3.63-3.76 (m, 1H)3.92-4.06 (m, 1H) 7.04-7.11 (m, 2H) 7.12-7.21 (m, 2H) 8.04 (t, J=7.8 Hz,1H CO₂H (not visible)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.87 (s, 3H) 1.09-1.17 (m, 3H) 1.32 (s,3H) 1.26-1.36 (m, 2H)1.38-1.51 (m, 1H) 1.41 (t, J=7.3 Hz, 3H) 1.53-1.86(m, 4H) 1.93 (br d, J=5.1 Hz, 1H) 1.96-2.12 (m, 1H) 2.38 (br d, J=5.6Hz, 1H) 3.04-3.17 (m, 1H) 3.19-3.28 (m, 2H) 3.49-3.59 (m, 1H) 3.35-4.52(m, 1H) 7.04-7.11 (m, 2H) 7.12-7.21 (m, 2H) 8.04 (t, J=7.8 Hz, 1H CO₂H(not visible)

Compound (W2)

Major diastereomer (60%)

1H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (d, J=6.3 Hz, 3H) 1.22-1.39 (m, 3H)1.44 (t, J=7.4 Hz, 3H) 1.55-1.85 (m, 4H) 1.91-2.10 (m, 1H) 2.94 (t,J=12.6 Hz, 1H) 3.27 (q, J=7.6 Hz, 2H) 3.67-3.75 (m, 1H) 4.00 (br d,J=13.2 Hz, 1H) 7.13 (d, J=7.9 Hz, 1H) 7.19 (d, J=7.8 Hz, 1H) 8.00 (dd,J=8.5, 1.6 Hz, 1H) 8.06 (dd, J=12.3, 1.6 Hz, 1H) 8.17 (s, 1H) 8.32 (t,J=8.45 Hz, 1H) 9.20 (s, 1H) 12.69-12.87 (m, 1H)

Minor diastereomer (40%)

1H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 (dd, J=6.3 Hz, 3H) 1.22-1.39 (m,3H) 1.44 (t, J=7.4 Hz, 3H) 1.55-1.85 (m, 4H) 1.91-2.10 (m, 1H) 3.13-3.17(m, 1H) 3.27 (q, J=7.6 Hz, 2H) 3.55 (br d, J=15.1 Hz, 1H) 4.45 (m, 1H)7.13 (d, J=7.9 Hz, 1H) 7.19 (d, J=7.8 Hz, 1H) 8.00 (dd, J=8.5, 1.6 Hz,1H) 8.06 (dd, J=12.3, 1.6 Hz, 1H) 8.17 (s, 1H) 8.32 (t, J=8.4 Hz, 1H)9.20 (s, 1H) 12.69-12.87 (m, 1H)

Compound (W13):

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.79 (br s, 1H) 9.20 (s, 1H) 8.29 (t,J=8.4 Hz, 1H) 8.16 (s, 1H) 8.05 (dd, J=12.3, 2.2 Hz, 1H) 7.99 (dd,J=8.7, 2.0 Hz, 1H) 7.17 (d, J=3.5 Hz, 1H) 7.13 (s, 1H) 4.00 (br d,J=13.2 Hz, 1H) 3.63-3.76 (m, 1H) 3.06-3.23 (m, 2H) 2.93 (t, J=12.5 Hz,1H) 2.41-2.48 (m, 1H) 1.89-1.99 (m, 1H) 1.22-1.85 (m, 7H) 1.12 (d, J=6.6Hz, 3H) 0.97-1.03 (m, 6H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.79 (br s, 1H) 9.20 (s, 1H) 8.29 (t,J=8.4 Hz, 1H) 8.16 (s, 1H) 8.05 (dd, J=12.3, 2.2 Hz, 1H) 7.99 (dd,J=8.7, 2.0 Hz, 1H) 7.18 (d, J=3.5 Hz, 1H) 7.15 (s, 1H) 4.37-4.50 (m, 1H)3.53 (br d, J=15.1 Hz, 1H) 3.06-3.23 (m, 3H) 2.41-2.48 (m, 1H) 2.02-2.12(m, 1H) 1.22-1.85 (m, 7H) 1.15 (d, J=6.3 Hz, 3H) 0.97-1.03 (m, 6H)

Compound (W14)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.58 (br s, 1H) 7.96 (t, J=8.8 Hz, 1H)6.99 (s, 1H) 6.91 (d, J=3.5 Hz, 1H) 6.55 (br d, J=8.8 Hz, 1H) 6.47 (brd, J=14.5 Hz, 1H) 3.99 (br d, J=13.2 Hz, 1H) 3.60-3.73 (m, 1H) 3.36-3.57(m, 3H) 3.24 (quin, J=7.0 Hz, 1H) 3.02-3.17 (m, 2H) 2.92 (br t, J=12.6Hz, 1H) 2.39-2.47 (m, 1H) 2.13-2.30 (m, 2H) 1.89-1.97 (m, 1H) 1.22-1.85(m, 8H) 1.11 (br d, J=6.3 Hz, 3H) 0.94-1.04 (m, 6H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.58 (br s, 1H) 7.96 (t, J=8.8 Hz, 1H)7.02 (s, 1H) 6.92 (d, J=3.8 Hz, 1H) 6.55 (br d, J=8.8 Hz, 1H) 6.47 (brd, J=14.5 Hz, 1H) 4.39-4.49 (m, 1H) 3.36-3.57 (m, 4H) 3.24 (quin, J=7.0Hz, 1H) 3.02-3.17 (m, 3H) 2.39-2.47 (m, 1H) 2.13-2.30 (m, 2H) 2.01-2.08(m, 1H) 1.22-1.85 (m, 8H) 1.15 (br d, J=6.3 Hz, 3H) 0.94-1.04 (m, 6H)

Compound (W15)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.96 (br t, J=8.5 Hz, 1H) 6.85-7.03 (m,3H) 6.51 (br d, J=8.2 Hz, 1H) 6.43 (br d, J=14.2 Hz, 1H) 4.00 (br d,J=12.6 Hz, 1H) 3.70-3.80 (m, 1H) 3.27-3.43 (m, 3H) 3.08-3.19 (m, 2H)2.92 (br t, J=12.5 Hz, 1H) 1.89-2.26 (m, 9H) 1.19-1.87 (m, 7H) 1.06-1.18(m, 3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.96 (br t, J=8.5 Hz, 1H) 6.85-7.03 (m,3H) 6.51 (br d, J=8.2 Hz, 1H) 6.43 (br d, J=14.2 Hz, 1H) 4.39-4.51 (m,1H) 3.60 (br d, J=14.5 Hz, 1H) 3.27-3.43 (m, 4H) 3.08-3.19 (m, 2H)1.89-2.26 (m, 9H) 1.19-1.87 (m, 7H) 1.06-1.18 (m, 3H)

Compound (W16)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.52 (br s, 1H) 7.88 (t, J=8.7 Hz, 1H)7.16 (s, 1H) 6.99 (s, 1H) 6.90 (d, J=3.5 Hz, 1H) 6.58 (dd, J=8.7, 1.7Hz, 1H) 6.44 (dd, J=14.2, 1.6 Hz, 1H) 3.98 (br d, J=13.2 Hz, 1H)3.66-3.77 (m, 1H) 3.21 (q, J=7.3 Hz, 2H) 2.92 (br t, J=12.6 Hz, 1H)1.89-1.98 (m, 1H) 1.53-1.86 (m, 4H) 1.46-1.52 (m, 2H) 1.40 (t, J=7.4 Hz,3H) 1.21-1.35 (m, 3H) 1.12 (d, J=6.3 Hz, 3H) 1.04-1.09 (m, 2H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.52 (br s, 1H) 7.88 (t, J=8.7 Hz, 1H)7.16 (s, 1H) 7.01 (s, 1H) 6.91 (d, J=3.5 Hz, 1H) 6.58 (dd, J=8.7, 1.7Hz, 1H) 6.44 (dd, J=14.2, 1.6 Hz, 1H) 4.37-4.48 (m, 1H) 3.54 (br d,J=15.4 Hz, 1H) 3.21 (q, J=7.3 Hz, 2H) 3.07-3.15 (m, 1H) 2.01-2.11 (m,1H) 1.53-1.86 (m, 4H) 1.46-1.52 (m, 2H) 1.40 (t, J=7.4 Hz, 3H) 1.21-1.35(m, 3H) 1.14 (d, J=6.3 Hz, 3H) 1.04-1.09 (m, 2H)

Compound (W17)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.64 (br s, 1H) 7.97 (t, J=8.8 Hz, 1H)6.98 (s, 1H) 6.91 (d, J=3.5 Hz, 1H) 6.51 (dd, J=8.8, 1.9 Hz, 1H) 6.44(br d, J=14.8 Hz, 1H) 3.99 (br d, J=13.2 Hz, 1H) 3.64-3.77 (m, 2H)3.36-3.46 (m, 2H) 3.15-3.28 (m, 3H) 2.92 (br t, J=12.6 Hz, 1H) 2.37-2.43(m, 1H) 1.86-2.11 (m, 2H) 1.53-1.85 (m, 4H) 1.41 (t, J=7.4 Hz, 3H) 1.34(s, 3H) 1.21-1.31 (m, 3H) 1.12 (d, J=6.3 Hz, 3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.64 (br s, 1H) 7.97 (t, J=8.8 Hz, 1H)7.00 (s, 1H) 6.92 (d, J=3.5 Hz, 1H) 6.51 (dd, J=8.8, 1.9 Hz, 1H) 6.44(br d, J=14.8 Hz, 1H) 4.38-4.49 (m, 1H) 3.64-3.77 (m, 1H) 3.54 (br d,J=15.4 Hz, 1H) 3.36-3.46 (m, 2H) 3.15-3.28 (m, 3H) 3.04-3.15 (m, 1H)2.37-2.43 (m, 1H) 1.86-2.11 (m, 2H) 1.53-1.85 (m, 4H) 1.41 (t, J=7.4 Hz,3H) 1.34 (s, 3H) 1.21-1.31 (m, 3H) 1.14 (d, J=6.3 Hz, 3H)

Compound (W18)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.63-13.30 (m, 1H) 7.95 (t, J=8.8 Hz,1H) 6.97 (s, 1H) 6.89 (d, J=3.5 Hz, 1H) 6.50 (dd, J=8.8, 1.9 Hz, 1H)6.42 (br d, J=14.5 Hz, 1H) 3.97 (br d, J=13.2 Hz, 1H) 3.55-3.73 (m, 4H)3.34-3.42 (m, 4H) 3.20 (q, J=7.6 Hz, 2H) 2.90 (br t, J=12.6 Hz, 1H)2.22-2.31 (m, 1H) 1.87-2.07 (m, 2H) 1.49-1.83 (m, 4H) 1.39 (t, J=7.4 Hz,3H) 1.16-1.37 (m, 3H) 1.10 (d, J=6.3 Hz, 3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.63-13.30 (m, 1H) 7.95 (t, J=8.8 Hz,1H) 6.98 (s, 1H) 6.91 (d, J=3.5 Hz, 1H) 6.50 (dd, J=8.8, 1.9 Hz, 1H)6.42 (br d, J=14.5 Hz, 1H) 4.31-4.49 (m, 1H) 3.55-3.73 (m, 3H) 3.52 (brd, J=15.4 Hz, 1H) 3.34-3.42 (m, 4H) 3.20 (q, J=7.6 Hz, 2H) 3.05-3.15 (m,1H) 2.22-2.31 (m, 1H) 1.87-2.07 (m, 2H) 1.49-1.83 (m, 4H) 1.39 (t, J=7.4Hz, 3H) 1.16-1.37 (m, 3H) 1.12 (d, J=6.3 Hz, 3H)

Compound (W19)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.87 (br t, J=9.0 Hz, 1H) 6.95 (s, 1H)6.84-6.91 (m, 1H) 6.51 (br d, J=8.5 Hz, 1H) 6.37 (br d, J=15.4 Hz, 1H)3.98 (br d, J=12.9 Hz, 1H) 3.66-3.75 (m, 1H) 3.57 (s, 2H) 3.17-3.28 (m,2H) 2.98 (s, 3H) 2.91 (br t, J=12.3 Hz, 1H) 1.89-1.99 (m, 1H) 1.54-1.83(m, 4H) 1.40 (br t, J=7.4 Hz, 3H) 1.20-1.35 (m, 3H) 1.13 (br d, J=6.3Hz, 3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.87 (br t, J=9.0 Hz, 1H) 6.97 (s, 1H)6.84-6.91 (m, 1H) 6.51 (br d, J=8.5 Hz, 1H) 6.37 (br d, J=15.4 Hz, 1H)4.34-4.49 (m, 1H) 3.57 (s, 2H) 3.47-3.56 (m, 1H) 3.06-3.28 (m, 3H) 2.98(s, 3H) 2.01-2.09 (m, 1H) 1.54-1.83 (m, 4H) 1.40 (br t, J=7.4 Hz, 3H)1.20-1.35 (m, 3H) 1.14 (br d, J=6.3 Hz, 3H)

Compound (W20)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.73 (br s, 1H) 8.74 (d, J=1.9 Hz, 1H)8.21 (br t, J=8.4 Hz, 1H) 7.96 (dd, J=8.8, 1.9 Hz, 1H) 7.49 (br d,J=12.6 Hz, 1H) 7.38 (br d, J=8.2 Hz, 1H) 7.09-7.18 (m, 2H) 6.82 (d,J=8.8 Hz, 1H) 4.00 (br d, J=13.9 Hz, 1H) 3.66-3.77 (5m, 1H) 3.54 (s, 3H)3.26 (q, J=7.3 Hz, 2H) 2.94 (br t, J=12.6 Hz, 1H) 1.89-2.02 (m, 1H)1.53-1.88 (m, 4H) 1.43 (t, J=7.4 Hz, 3H) 1.22-1.38 (m, 3H) 1.12-1.20 (m,3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.73 (br s, 1H) 8.74 (d, J=1.9 Hz, 1H)8.21 (br t, J=8.4 Hz, 1H) 7.96 (dd, J=8.8, 1.9 Hz, 1H) 7.49 (br d,J=12.6 Hz, 1H) 7.38 (br d, J=8.2 Hz, 1H) 7.09-7.18 (m, 2H) 6.82 (d,J=8.8 Hz, 1H) 4.41-4.50 (m, 1H) 3.55-3.59 (m, 1H) 3.54 (s, 3H) 3.26 (q,J=7.3 Hz, 2H) 3.10-3.19 (m, 1H) 2.02-2.11 (m, 1H) 1.53-1.88 (m, 4H) 1.43(t, J=7.4 Hz, 3H) 1.22-1.38 (m, 3H) 1.12-1.20 (m, 3H)

Compound (W21)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.69 (br s, 1H) 7.97 (br t, J=8.5 Hz,1H) 6.97 (s, 1H) 6.91 (br d, J=3.2 Hz, 1H) 6.79 (br d, J=8.8 Hz, 1H)6.69 (br d, J=13.2 Hz, 1H) 6.54 (s, 1H) 3.92 (br d, J=13.6 Hz, 1H) 3.73(s, 3H) 3.71 (s, 3H) 3.58-3.67 (m, 1H) 3.16 (q, J=7.1 Hz, 2H) 2.86 (brt, J=12.6 Hz, 1H) 1.82-1.92 (m, 1H) 1.47-1.81 (m, 4H) 1.34 (t, J=7.4 Hz,3H) 1.11-1.29 (m, 3H) 1.06 (br d, J=6.3 Hz, 3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.69 (br s, 1H) 7.97 (br t, J=8.5 Hz,1H) 6.98 (s, 1H) 6.92 (br d, J=3.2 Hz, 1H) 6.79 (br d, J=8.8 Hz, 1H)6.69 (br d, J=13.2 Hz, 1H) 6.54 (s, 1H) 4.32-4.43 (m, 1H) 3.73 (s, 3H)3.71 (s, 3H) 3.43-3.51 (m, 1H) 3.16 (q, J=7.1 Hz, 2H) 3.00-3.10 (m, 1H)1.93-2.05 (m, 1H) 1.47-1.81 (m, 4H) 1.34 (t, J=7.4 Hz, 3H) 1.11-1.29 (m,3H) 1.08 (br d, J=6.6 Hz, 3H)

Compound (W22)

Major rotamer (60%)

¹H NMR (500 MHz, chloroform-d) δ ppm 8.05 (t, J=8.8 Hz, 1H) 7.04-7.08(m, 1H) 6.85 (s, 1H) 6.63 (dd, J=8.7, 2.4 Hz, 1H) 6.51 (dd, J=14.5, 2.2Hz, 1H) 4.45 (quin, J=8.0 Hz, 1H) 4.23 (br d, J=13.9 Hz, 1H) 3.96-4.11(m, 1H) 3.28 (q, J=7.5 Hz, 2H) 3.01-3.14 (m, 1H) 2.93 (s, 3H) 2.80-2.91(m, 1H) 2.61-2.73 (m, 2H) 2.45-2.58 (m, 2H) 1.97-2.06 (m, 1H) 1.64-1.96(m, 4H) 1.49 (t, J=7.4 Hz, 3H) 1.32-1.45 (m, 3H) 1.22 (d, J=6.3 Hz, 3H)

Minor rotamer (40%)

¹H NMR (500 MHz, chloroform -d) δ ppm 8.05 (t, J=8.8 Hz, 1H) 7.04-7.08(m, 1H) 6.89 (s, 1H) 6.63 (dd, J=8.7, 2.4 Hz, 1H) 6.51 (dd, J=14.5, 2.2Hz, 1H) 4.62-4.71 (m, 1H) 4.45 (quin, J=8.0 Hz, 1H) 3.89 (br d, J=14.8Hz, 1H) 3.28 (q, J=7.5 Hz, 2H) 3.01-3.14 (m, 2H) 2.93 (s, 3H) 2.61-2.73(m, 2H) 2.45-2.58 (m, 2H) 2.08-2.17 (m, 1H) 1.64-1.96 (m, 4H) 1.49 (t,J=7.4 Hz, 3H) 1.32-1.45 (m, 3H) 1.24 (d, J=6.3 Hz, 3H)

Compound (W23)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.28 (br s, 1H) 7.96 (t, J=9.0 Hz, 1H)7.00 (s, 1H) 6.93 (d, J=3.5 Hz, 1H) 6.75 (dd, J=9.0, 2.0 Hz, 1H) 6.68(br d, J=15.1 Hz, 1H) 4.21 (quin, J=8.4 Hz, 1H) 3.99 (br d, J=13.2 Hz,1H) 3.66-3.75 (m, 1H) 3.22 (q, J=7.4 Hz, 2H) 2.85-2.96 (m, 4H) 2.71-2.81(m, 1H) 2.51-2.56 (m, 2 H, partially obscured by solvent peak) 2.22-2.33(m, 2H) 1.88-1.98 (m, 1H) 1.52-1.86 (m, 4H) 1.41 (t, J=7.4 Hz, 3H)1.20-1.37 (m, 3H) 1.12 (d, J=6.3 Hz, 3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.28 (br s, 1H) 7.96 (t, J=9.0 Hz, 1H)7.02 (s, 1H) 6.92 (d, J=3.5 Hz, 1H) 6.75 (dd, J=9.0, 2.0 Hz, 1H) 6.68(br d, J=15.1 Hz, 1H) 4.32-4.43 (m, 1H) 4.21 (quin, J=8.4 Hz, 1H) 3.53(br d, J=15.1 Hz, 1H) 3.22 (q, J=7.4 Hz, 2H) 3.05-3.16 (m, 1H) 2.89 (s,3H) 2.71-2.81 (m, 1H) 2.51-2.56 (m, 2 H, partially obscured by solventpeak) 2.22-2.33 (m, 2H) 1.98-2.11 (m, 1H) 1.52-1.86 (m, 4H) 1.41 (t,J=7.4 Hz, 3H) 1.20-1.37 (m, 3H) 1.14 (d, J=6.3 Hz, 3H)

Compound (W24)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.71 (br s, 2H) 9.15 (s, 1H) 8.25 (t,J=8.5 Hz, 1H) 8.13 (s, 1H) 7.84-8.04 (m, 2H) 6.41 (br s, 1H) 5.13-5.42(m, 1H) 3.92 (br d, J=12.9 Hz, 1H) 3.76-3.85 (m, 1H) 2.71-3.11 (m, 1H)1.90-2.05 (m, 1H) 1.34-1.84 (m, 4H) 1.17-1.32 (m, 3H) 1.08 (br d, J=5.7Hz, 3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.71 (br s, 2H) 9.15 (s, 1H) 8.25 (t,J=8.5 Hz, 1H) 8.13 (s, 1H) 7.84-8.04 (m, 2H) 6.41 (br s, 1H) 5.13-5.42(m, 1H) 4.28-4.59 (m, 1H) 3.57-3.70 (m, 1H) 2.71-3.11 (m, 1H) 1.90-2.05(m, 1H) 1.34-1.84 (m, 4H) 1.17-1.32 (m, 3H) 1.08 (br d, J=5.7 Hz, 3H)

Compound (W25)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (d, J=6.3 Hz, 3H) 1.21-1.38 (m, 3H)1.43 (t, J=7.4 Hz, 3H) 1.57 (br s, 1H) 1.60-1.83 (m, 3H) 1.93-1.99 (m,1H) 2.44-2.47 (s, 3H) 2.93 (br t, J=12.6 Hz, 1H) 3.22-3.31 (m, 2H)3.66-3.74 (m, 1H) 3.99 (br d, J=13.2 Hz, 1H) 7.11 (d, J=7.9 Hz, 1H) 7.16(d, J=7.7 Hz, 1H) 7.94 (d, J=8.4 Hz, 1H) 7.98-8.01 (d, J=12,6 Hz, 1H)8.27 (t, J=8.4 Hz, 1H) 9.08 (s, 1H) 12.60 (m, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.3 Hz, 3H) 1.21-1.38 (m, 3H)1.43 (t, J=7.4 Hz, 3H) 1.57 (br s, 1H) 1.60-1.83 (m, 3H) 2.06 (m, 1H)2.44-2.47 (s, 3H) 3.09-3.18 (m, 1H) 3.22-3.31 (m, 2H) 3.54 (br d, J=15.1Hz, 1H) 4.44 (dt, J=12.0, 6.0 Hz, 1H) 7.11 (d, J=7.9 Hz, 1H) 7.16 (dd,J=7.9 Hz, 1H) 7.94 (d, J=8.4 Hz, 1H) 7.98-8.01 (d, J=12,6 Hz, 1H) 8.27(t, J=8.4Hz, 1H) 9.08 (s, 1H) 12.60 (m, 1H)

Compound (W33)

Major rotamer 63%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.21-1.41 (m, 4H) 1.53 (d, J=6.6 Hz, 3H)2.70-2.75 (m, 1H) 2.86-3.06 (m, 2H) 3.45-3.51 (m, 1H) 3.73-3.91 (m, 1H)5.60 (q, J=6.6 Hz, 1H) 6.90-6.96 (m, 1H) 7.08-7.34 (m, 5H) 7.99-8.10 (m,2H) 8.17 (s, 1H) 8.35 (br t, J=8.5 Hz, 1H) 9.21 (s, 1H) 12.79 (br s, 1H)

minor rotamer 37%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.21-1.41 (m, 4H) 1.56 (d, J=6.6 Hz, 3H)2.70-2.75 (m, 1H) 2.86-3.06 (m, 2H) 3.45-3.51 (m, 1H) 4.55-4.58 (m , 1H)4.97 (q, J=6.9 Hz, 1H) 6.90-6.96 (m, 1H) 7.08-7.34 (m, 5H) 7.99-8.10 (m,2H) 8.17 (s, 1H) 8.35 (br t, J=8.5 Hz, 1H) 9.21 (s, 1H) 12.79 (br s, 1H)

Compound (W35)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.13 (d, J=6.6 Hz, 3H) 1.20-1.38 (m, 3H)1.43 (t, J=7.3 Hz, 3H) 1.52-1.87 (m, 4H) 1.92-2.13 (m, 1H) 2.93 (t,J=12.1 Hz, 1H) 3.21-3.30 (m, 2H) 3.64-3.78 (m, 1H) 3.95-4.05 (m, 1H)7.11 (s, 1H) 7.17 (d, J=3.5 Hz, 1H) 7.94 (dd, J=8.6, 2.0 Hz, 1H) 8.03(dd, J=12.4, 2.3 Hz, 1H) 8.31 (t, J=8.34 Hz, 1H) 9.27 (s, 1H) 13.08 (brs, 1H)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (d, J=6.6 Hz, 3H) 1.20-1.38 (m, 3H)1.43 (t, J=7.3 Hz, 3H) 1.52-1.87 (m, 4H) 1.92-2.13 (m, 1H) 3.08-3.16 (m,1H) 3.21-3.30 (m, 2H) 3.49-3.60 (m, 1H) 4.39-4.53 (m, 1H) 7.13 (s, 1H)7.19 (d, J=3.5 Hz, 1H) 7.94 (dd, J=8.6, 2.0 Hz, 1H) 8.03 (dd, J=12.4,2.3 Hz, 1H) 8.31 (t, J=8.3 Hz, 1H) 9.27 (s, 1H) 13.08 (br s, 1H)

Compound (W36)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.07-1.11 (m, 3H) 1.13-1.43 (m, 3H)1.46-1.78 (m, 4H) 1.87 (s, 3H) 1.89-2.03 (m, 1H) 2.88 (br t, J=12.6 Hz,1H) 3.60-3.76 (m, 1H) 3.93 (br d, J=14.2 Hz, 1H) 4.63 (br d, J=6.3 Hz,2H) 5.04 (d, J=6.6 Hz, 2H) 7.09 (s, 1H) 7.13 (dd, J=7.9, 3.2 Hz, 1H)7.90 (dd, J=8.7, 1.7 Hz, 1H) 7.94-8.00 (m, 1H) 8.09 (s, 1H) 8.16 (t,J=8.2 Hz, 1H) 9.12 (s, 1H) 12.72 (br s, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.07-1.11 (m, 3H) 1.13-1.43 (m, 3H)1.46-1.78 (m, 4H) 1.87 (s, 3H) 1.89-2.03 (m, 1H) 3.02-3.15 (m, 1H) 3.47(br d, J=16.1 Hz, 1H) 4.32-4.41 (m, 1H) 4.63 (br d, J=6.3 Hz, 2H) 5.04(d, J=6.6 Hz, 2H) 7.09 (s, 1H) 7.13 (dd, J=7.9, 3.2 Hz, 1H) 7.90 (dd,J=8.7, 1.7 Hz, 1H) 7.94-8.00 (m, 1H) 8.09 (s, 1H) 8.16 (t, J=8.2 Hz, 1H)9.12 (s, 1H) 12.72 (br s, 1H)

Compound (W37)

Major rotamer 65%

¹H NMR (500 MHz, DMSO-d₆) 6 1.25-1.35 (m, 5H) 1.46 (d, J=6.6 Hz, 3H)2.14-2.33 (m, 2H) 2.75 (br d, J=15.5 Hz, 1H) 2.81-3.00 (m, 2H) 3.17-3.29(m, 1H) 3.36-3.57 (m, 4H) 3.93 (br dd, J=13.9, 5.0 Hz, 1H) 5.53 (q,J=6.7 Hz, 1H) 6.48 (br d, J=14.8 Hz, 1H) 6.55 (br d, J=8.8 Hz, 1H)6.77-6.83 (m, 1H) 6.91-6.98 (m, 1H) 7.02 (d, J=5.0 Hz, 1H) 7.39 (d,J=5.0 Hz, 1H) 8.01 (t, J=8.3 Hz, 1H) 12.50-12.72 (m, 1H)

Minor rotamer 35%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.25-1.35 (m, 5H) 1.51 (d, J=6.6 Hz, 3H)2.14-2.33 (m, 2H) 2.81-3.00 (m, 2H) 3.17-3.29 (m, 2H) 3.36-3.57 (m, 4H)4.71 (br dd, J=12.6, 4.7 Hz, 1H) 4.90 (br d, J=6.3 Hz, 1H) 6.48 (br d,J=14.8 Hz, 1H) 6.55 (br d, J=8.83 Hz, 1H) 6.77-6.83 (m, 2H) 6.91-6.98(m, 1H) 7.30 (d, J=5.0 Hz, 1H) 8.01 (t, J=8.32 Hz, 1H) 12.50-12.72 (m,1H)

Compound (W38)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20-1.38 (m, 4H) 1.52 (d, J=6.6 Hz, 3H)2.13-2.34 (m, 2H) 2.52-2.55 (m, 1H) 2.65-2.76 (m, 1H) 2.83-3.06 (m, 2H)3.17-3.29 (m, 1H) 3.33-3.57 (m, 4H) 3.81 (br dd, J=13.4, 4.8 Hz, 1H)5.58 (q, J=6.6 Hz, 1H) 6.48 (d, J=14.7 Hz, 2.20 Hz, 1H) 6.54 (d, J=9.1Hz, 1.52 Hz, 1H) 6.76-6.83 (m, 1H) 6.91-6.96 (m, 1H) 7.06-7.34 (m, 4H)8.00 (t, J=8.8 Hz, 1H) 12.55 (br s, 1H)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20-1.38 (m, 4H) 1.55 (d, J=7.1 Hz, 3H)2.13-2.34 (m, 2H) 2.52-2.55 (m, 1H) 2.65-2.76 (m, 1H) 2.83-3.06 (m, 2H)3.17-3.29 (m, 1H) 3.33-3.57 (m, 4H) 4.51-4.58 (m, 1H) 4.96 (d, J=6.6 Hz,1H) 6.48 (d, J=14.7 Hz, 2.2 Hz, 1H) 6.54 (d, J=9.1 Hz, 1.52 Hz, 1H)6.76-6.83 (m, 1H) 6.91-6.96 (m, 1H) 7.06-7.34 (m, 4H) 8.00 (t, J=8.8 Hz,1H) 12.55 (br s, 1H)

Compound (W39)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.94-1.05 (m, 2H) 1.16-1.31 (m, 2H) 1.48(d, J=6.6 Hz, 3H) 1.63-1.68 (m, 3H) 2.72-3.05 (m, 2H) 3.31-3.48 (m, 1H)4.02 (br dd, J=13.4, 4.8 Hz, 1H) 5.56 (d, J=6.6 Hz, 1H) 7.02 (d, J=5.1Hz, 1H) 7.13-7.18 (m, 1H) 7.23 (d, J=3.5 Hz, 1H) 7.38 (d, J=5.1 Hz, 1H)7.98-8.07 (m, 2H) 8.16 (s, 1H) 8.32 (t, J=8.2 Hz, 1H) 9.18 (s, 1H) 12.73(br s, 1H)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.94-1.05 (m, 2H) 1.16-1.31 (m, 2H) 1.54(d, J=6.6 Hz, 3H) 1.63-1.68 (m, 3H) 2.72-3.05 (m, 2H) 4.68-4.77 (m, 1H)4.99 (d, J=6.6 Hz, 1H) 5.56 (d, J=6.6 Hz, 1H) 6.80 (d, J=5.6 Hz, 1H)7.13-7.18 (m, 1H) 7.23 (d, J=3.5 Hz, 1H) 7.30 (d, J=5.1 Hz, 1H)7.98-8.07 (m, 2H) 8.16 (s, 1H) 8.32 (t, J=8.2 Hz, 1H) 9.18 (s, 1H) 12.73(br s, 1H)

Compound (W40)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39-1.56 (m, 6H) 2.75-3.04 (m, 2H)3.21-3.30 (m, 2H) 3.45 (br t, J=10.6 Hz, 1H) 3.98-4.07 (m, 1H) 5.54-5.60(m, 1H) 7.03 (d, J=5.6 Hz, 1H) 7.17-7.25 (m, 2H) 7.39 (d, J=4.6 Hz, 1H)7.96-8.09 (m, 2H) 8.15 (s, 1H) 8.32 (br t, J=8.3 Hz, 1H) 9.19 (s, 1H)12.75 (br s, 1H)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39-1.56 (m, 6H) 2.75-3.04 (m, 3H)3.21-3.30 (m, 2H) 4.73 (br d, J=10.1 Hz, 1H) 4.98 (br d, J=7.1 Hz, 1H)6.80 (d, J=5.1 Hz, 1H) 7.17-7.25 (m, 2H) 7.30 (d, J=5.6 Hz, 1H)7.96-8.09 (m, 2H) 8.15 (s, 1H) 8.32 (br t, J=8.3 Hz, 1H) 9.19 (s, 1H)12.75 (br s, 1H)

Compound (W43)

Major rotamer 60%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35-1.45 (m, 3H) 1.47 (d, J=7.1 Hz, 3H)2.15-2.31 (m, 2H) 2.73-2.81 (m, 1H) 2.84-3.03 (m, 1H) 3.19-3.27 (m, 3H)3.32-3.56 (m, 5H) 3.98-4.06 (m, 1H) 5.52-5.58 (m, 1H) 6.45-6.57 (m, 2H)6.95-6.98 (m, 1H) 7.02 (d, J=5.6 Hz, 1H) 7.05-7.11 (m, 1H) 7.38 (d,J=5.1 Hz, 1H) 7.99 (t, J=8.8 Hz, 1H) 12.54 (br s, 1H)

Minor rotamer 40%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35-1.45 (m, 3H) 1.52 (d, J=6.6 Hz, 3H)2.15-2.31 (m, 2H) 2.84-3.03 (m, 2H) 3.19-3.27 (m, 4H) 3.32-3.56 (m, 4H)4.69-4.76 (m, 1H) 4.94-5.01 (m, 1H) 6.45-6.57 (m, 2H) 6.80 (d, J=5.6 Hz,1H) 6.95-6.98 (m, 1H) 7.05-7.11 (m, 1H) 7.29 (d, J=5.1 Hz, 1H) 7.99 (t,J=8.8 Hz, 1H) 12.54 (br s, 1H)

Compound (W44)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.93-1.01 (m, 2H) 1.16-1.30 (m, 3H) 1.47(d, J=6.6 Hz, 3H) 1.59-1.69 (m, 3H) 2.15-2.32 (m, 2H) 2.74-2.81 (m, 1H)2.92-3.04 (m, 1H) 3.17-3.31 (m, 1H) 3.36-3.57 (m, 4H) 4.01 (br dd,J=13.4, 4.6 Hz, 1H) 5.55 (q, J=6.6 Hz, 1H) 6.49 (br d, J=14.5 Hz, 1H)6.58 (br d, J=9.1 Hz, 1H) 6.97-7.07 (m, 3H) 7.39 (d, J=5.0 Hz, 1H) 8.01(t, J=8.8 Hz, 1H) 12.58 (br s, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.93-1.01 (m, 2H) 1.16-1.30 (m, 3H) 1.54(d, J=6.6 Hz, 3H) 1.59-1.69 (m, 3H) 2.15-2.32 (m, 2H) 2.83-2.92 (m, 2H)3.17-3.31 (m, 2H) 3.36-3.57 (m, 3H) 4.72 (br dd, J=12.8 Hz, 4.3, 1H)4.97 (q, J=6.6 Hz, 1H) 6.49 (br d, J=14.5 Hz, 1H) 6.58 (br d, J=9.1 Hz,1H) 6.80 (d, J=5.4 Hz, 1H) 6.97-7.07 (m, 2H) 7.30 (d, J=5.0 Hz, 1H) 8.01(t, J=8.8 Hz, 1H) 12.58 (br s, 1H)

Compound (W46)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (d, 6.3 Hz, 3H) 1.22-1.38 (m, 2H)1.62-1.83 (m, 4H) 1.89-1.99 (m, 1H) 2.14-2.30 (m, 2H) 2.93 (br t, J=12.6Hz, 1H) 3.09-3.27 (m, 6H) 3.35-3.42 (m, 2H) 3.46-3.57 (m, 2H) 3.65-3.72(m, 1H) 3.99 (br d, J=13.2 Hz, 1H) 4.09 (q, J=8.7 Hz, 1H) 6.45-6.50 (m,1H) 6.54 (d, J=8.6 Hz, 1H) 6.96 (dd, J=7.9, 3.5 Hz, 1H) 7.19 (s, 1H)8.00 (t, J=8.8 Hz, 1H) 12.58 (br s, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (d, 6.3 Hz, 3H) 1.22-1.48 (m, 4H)1.62-1.83 (m, 4H) 2.00-2.10 (m, 1H) 2.14-2.30 (m, 2H) 3.09-3.27 (m, 5H)3.35-3.42 (m, 2H) 3.46-3.57 (m, 3H) 4.09 (quin, J=8.7 Hz, 1H) 4.41-4.48(m, 1H) 6.45-6.50 (m, 1H) 6.54 (d, J=8.6 Hz, 1H) 6.96 (dd, J=7.9, 3.5Hz, 1H) 7.19 (s, 1H) 8.00 (t, J=8.8 Hz, 1H) 12.58 (br s, 1H)

Compound (W47)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.31-1.46 (m, 6H) 1.54 (d, J=6.6 Hz, 3H)1.87-1.97 (m, 1H) 2.37-2.44 (m, 1H) 2.75 (br d, J=16.4 Hz, 1H) 3.10-3.09(m, 1H) 3.16-3.30 (m, 3H) 3.36-3.53 (m, 3H) 3.74 (br d, J=9.8 Hz, 1H)3.91 (br dd, J=12.9, 3.8 Hz, 1H) 5.61 (br q, J=6.9 Hz, 1H) 6.46 (br d,J=14.2 Hz, 1H) 6.53 (br d, J=8.8 Hz, 1H) 6.94-7.00 (m, 1H) 7.05-7.26 (m,4H) 7.34 (br d, J=7.3 Hz, 1H) 7.99 (br t, J=8.7 Hz, 1H) 12.64 (br s, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.31-1.46 (m, 6H) 1.58 (d, J=6.6 Hz, 3H)1.87-1.97 (m, 1H) 2.37-2.44 (m, 1H) 2.82-2.99 (m, 2H) 3.16-3.30 (m, 3H)3.36-3.53 (m, 3H) 3.74 (br d, J=9.8 Hz, 1H) 4.58 (br d, J=15.8 Hz, 1H)5.04 (br q, J=6.3 Hz, 1H) 6.46 (br d, J=14.2 Hz, 1H) 6.53 (br d, J=8.8Hz, 1H) 6.94-7.00 (m, 1H) 7.05-7.26 (m, 5H) 7.99 (br t, J=8.7 Hz, 1H)12.64 (br s, 1H)

Compound (W48)

Major rotamer 63%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.35 (s, 3H) 1.38-1.45 (m, 3H) 1.48 (d,J=6.6 Hz, 3H) 1.88-2.03 (m, 1H) 2.32-2.46 (m, 1H) 2.75-3.03 (m, 2H) 3.18(d, J=9.8 Hz, 1H) 3.21-3.28 (m, 2H) 3.36-3.47 (m, 3H) 3.74 (d, J=9.8 Hz,1H) 4.02 (br dd, J=13.4, 4.9 Hz, 1H) 5.56 (q, J=6.6 Hz, 1H) 6.46 (br d,J=14.8 Hz, 1H) 6.53 (br d, J=8.8 Hz, 1H) 6.96-6.98 (m, 1H) 7.03 (d,J=5.0 Hz, 1H) 7.11 (s, 1H) 7.39 (d, J=5.0 Hz, 1H) 7.99 (td, J=8.8, 2.4Hz, 1H) 12.63 (br s, 1H)

Minor rotamer 37%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.35 (s, 3H) 1.38-1.45 (m, 3H) 1.53 (d,J=6.6 Hz, 3H) 1.88-2.03 (m, 1H) 2.32-2.46 (m, 1H) 2.75-3.03 (m, 2H) 3.18(d, J=9.8 Hz, 1H) 3.21-3.28 (m, 2H) 3.36-3.47 (m, 3H) 3.74 (d, J=9.8 Hz,1H) 4.73 (br dd, J=12.8, 4.3 Hz, 1H) 4.97 (q, J=6.6 Hz, 1H) 6.46 (br d,J=14.8 Hz, 1H) 6.53 (br d, J=8.8 Hz, 1H) 6.81 (d, J=5.0 Hz, 1H)6.96-6.98 (m, 1H) 7.07 (s, 1H) 7.30 (d, J=5.0 Hz, 1H) 7.99 (td, J=8.8,2.4 Hz, 1H) 12.63 (br s, 1H)

Compound (W49)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.11-1.32 (m, 5H) 1.35 (s, 3H) 1.41 (brt, J=7.41 Hz, 3H) 1.46-2.21 (m, 7H) 2.39-2.44 (m, 1H) 2.92 (br t,J=12.77 Hz, 1H) 3.10-3.30 (m, 3H) 3.36-3.46 (m, 2H) 3.66-3.77 (m, 2H)3.95-4.03 (m, 1H) 6.45 (br d, J=15.13 Hz, 1H) 6.52 (br d, J=8.51 Hz, 1H)6.92 (dd, J=7.25, 3.47 Hz, 1H) 7.00 (br d, J=8.51 Hz, 1H) 7.97 (br t,J=8.83 Hz, 1H) 12.63 (br s, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.11-1.32 (m, 5H) 1.35 (s, 3H) 1.41 (brt, J=7.41 Hz, 3H) 1.46-2.21 (m, 7H) 2.39-2.44 (m, 1H) 3.10-3.30 (m, 4H)3.36-3.46 (m, 2H) 3.49-3.62 (m, 1H) 3.66-3.77 (m, 1H) 4.40-4.48 (m, 1H)6.45 (br d, J=15.13 Hz, 1H) 6.52 (br d, J=8.51 Hz, 1H) 6.92 (dd, J=7.25,3.47 Hz, 1H) 7.00 (br d, J=8.51 Hz, 1H) 7.97 (br t, J=8.83 Hz, 1H) 12.63(br s, 1H)

Compound (W41)

Major diastereomer (65%)

1H NMR (500 MHz, DMSO-d₆) δ ppm 1.22-1.40 (m, 4H) 1.47 (d, J=6.6 Hz, 3H)2.76 (dd, J=15.5, 1.9 Hz, 1H) 2.83-3.03 (m, 2H) 3.43 (m, 1H) 3.94 (brdd, J=13.6, 5.0 Hz, 1H) 5.55 (q, J=6.6 Hz, 1H) 6.94 (s, 1H) 7.03 (d,J=5.0 Hz, 1H) 7.20 (m, 1H) 7.39 (d, J=5.4 Hz, 1H) 8.01 (d, J=8.4 Hz, 1H)8.07 (d, J=12.6 Hz 1H) 8.17 (s, 1H) 8.35 (td, J=8.4, 3.5 Hz, 1H) 9.21(s, 1H) 12.75 (br s, 1H)

Minor diastereomer (35%)

1H NMR (500 MHz, DMSO-d₆) δ ppm 1.22-1.40 (m, 4H) 1.51 (d, J=6.6 Hz, 3H)2.83-3.03 (m, 3H) 3.23 (td, J=12.3, 4.4 Hz, 1H) 4.72 (br dd, J=12.6, 4.7Hz, 1H) 4.91 (q, J=6.6 Hz, 1H) 6.80 (d, J=5.0 Hz, 1H) 6.92 (s, 1H) 7.20(m, 1H) 7.31 (d, J=5.0 Hz, 1H) 8.01 (d, J=8.4 Hz, 1H) 8.07 (d, J=12.6 Hz1H) 8.17 (s, 1H) 8.35 (td, J=8.4, 3.5 Hz, 1H) 9.21 (s, 1H) 12.75 (br s,1H)

Compound (W50)

Major rotamer 60%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.11-1.32 (m, 5H) 1.35 (s, 3H) 1.41 (brt, J=7.4 Hz, 3H) 1.46-2.21 (m, 7H) 2.39-2.44 (m, 1H) 2.92 (br t, J=12.8Hz, 1H) 3.10-3.30 (m, 3H) 3.36-3.46 (m, 2H) 3.66-3.77 (m, 2H) 3.95-4.03(m, 1H) 6.45 (br d, J=15.1 Hz, 1H) 6.52 (br d, J=8.5 Hz, 1H) 6.92 (dd,J=7.3, 3.5 Hz, 1H) 7.00 (br d, J=8.5 Hz, 1H) 7.97 (br t, J=8.8 Hz, 1H)12.63 (br s, 1H)

Minor rotamer 40%

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.11-1.32 (m, 5H) 1.35 (s, 3H) 1.41 (brt, J=7.4 Hz, 3H) 1.46-2.21 (m, 7H) 2.39-2.44 (m, 1H) 3.10-3.30 (m, 4H)3.36-3.46 (m, 2H) 3.49-3.62 (m, 1H) 3.66-3.77 (m, 1H) 4.40-4.48 (m, 1H)6.45 (br d, J=15.1 Hz, 1H) 6.52 (br d, J=8.5 Hz, 1H) 6.92 (dd, J=7.3,3.5 Hz, 1H) 7.00 (br d, J=8.5 Hz, 1H) 7.97 (br t, J=8.83 Hz, 1H) 12.63(br s, 1H)

Compound (W51)

Major rotamer (60%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.59 (br s, 1H) 7.99 (t, J=8.8 Hz, 1H)6.89 (d, J=3.5 Hz, 1H) 6.72 (s, 1H) 6.54 (br d, J=8.8 Hz, 1H) 6.48 (brd, J=14.8 Hz, 1H) 3.96 (br d, J=13.2 Hz, 1H) 3.45-3.57 (m, 3H) 3.36-3.41(m, 2H) 3.23 (quin, J=7.2 Hz, 1H) 2.85-2.98 (m, 2H) 2.12-2.32 (m, 2H)1.87-1.99 (m, 1H) 1.50-1.84 (m, 4H) 1.20-1.47 (m, 7H) 1.09 (d, J=6.3 Hz,3H)

Minor rotamer (40%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.59 (br s, 1H) 7.99 (t, J=8.8 Hz, 1H)6.91 (d, J=3.5 Hz, 1H) 6.73 (s, 1H) 6.54 (br d, J=8.8 Hz, 1H) 6.48 (brd, J=14.8 Hz, 1H) 4.36-4.45 (m, 1H) 3.42-3.69 (m, 2H) 3.36-3.41 (m, 2H)3.23 (quin, J=7.2 Hz, 1H) 3.05-3.13 (m, 1H) 2.85-2.98 (m, 2H) 2.12-2.32(m, 2H) 2.00-2.10 (m, 1H) 1.50-1.84 (m, 4H) 1.20-1.47 (m, 7H) 1.13 (d,J=6.3 Hz, 3H)

Melting Points

For a number of compounds, melting points (m.p.) were determined with aDSC 1 (Mettler Toledo). Melting points were measured with a temperaturegradient of 10° C./minute. Maximum temperature was 350° C. The reportedvalues are peak values. Values are obtained with experimentaluncertainties that are commonly associated with this analytical method.

LC/MS For LCMS-characterization of the compounds of the presentinvention, the following methods were used:

-   Instrument Configuration : Shimadzu Analytical HPLC SCL10Avp, Auto    Sampler Gilson 215, ELSD (evaporative light scattering detector)    Sedex 75, Mass Spectrometr PE SCIEX API 150, Analyst 1.3.1-   Column: Waters XBridge C18 3.5 u, 4.6×100 mm-   Gradient Flow Rate: 0.9 ml/min-   Mobile Phase: A: Water with 0.05% TFA    -   B: Acetonitrile 0.05% TFA-   Gradient: 0.01 min controller start;    -   8.00 min pump B %-90.0;    -   10.05 min pump B %-90.0;    -   10.10 min pump B %-5.0;    -   10.15 min controller stop;-   Sample Injection: 3.0-5.0 (1 mg/ml CH₃CN/H₂O)-   MS Detection: electrospray+ive ion (100-1100 range)-   UV detection wave-length: nm: 220, 254.

TABLE melting point and LC/MS date (retention time, theoreticalmolecular weight (MW theor) and (MH)⁺ peak) Co. No. mp° C. Rt min MWtheor MH⁺ A1 110-120 2.95 368.167 369.1 A2 193-194 2.72 405.253 406.4 A3135-136 3.08 396.172 397.1 A4 120-125 2.96 380.201 381.4 A5 oil 3.38368.258 369.2 A6 84 3.66 423.243 424.3 A7 195-197 3.3 401.222 402.2 A8230-235 6.37 417.216 418.3 A9 225-230 7.03 431.232 432.3 A10 155 2.84417.55 418.7 A11 170-175 2.23 413.56 414.4 A12 195-200 5.37 427.237428.3 A13 145-150 5.07 402.217 403.2 A14 115 5.21 416.232 417.5 A15 1756.63 429.216 430.5 A16 oil 3.24 382.217 383.5 A17 oil 3.28 382.217 383.5F3 185 3 440.232 441.55 F4 167-168 6.27 457.228 458.2 F5 75-76 7.4446.223 447.6 F6 oil 7.76 446.223 447.5 F7 95-96 8.67 475.218 476.5 F886-87 8.73 475.218 476.5 F9 65-67 7.81 460.239 461.5 F10 118-119 6.14474.254 475.5 F11 oil 5.69 474.254 475.6 F12 oil 8.51 486.254 487.6 F13oil 6.05 460.239 461.5 F14 245-250 8.16 501.218 502.4 F15 181-182 8.19501.218 502.4 F16 oil 5.95 446.223 447.5 F17 140-145 8.4 472.239 473.6F18 165-170 9.01 521.19 522.4 G1 195-200 7.31 424.208 425.4 A18 125-1303.28 394.217 395.5 A19 207-208 2.02 446.279 447.3 A20 oil 3.03 448.264449 A21 155-160 2.5 392.221 393.3 A22 — 2.78 442.225 443.3 A24 145-1506.9 431.212 432.4 A25 155-160 2.26 405.216 406.4 A26 160-165 2.72405.216 406.3 A27 160-165 2.47 391.201 392.2 A28 140-145 2.63 393.216394.2 A29 170-175 2.29 419.232 420.6 A30 165-170 2.32 419.232 420.3 A31185-190 7.41 465.197 466.1 A32 122 7.66 438.207 439.4 B1 140 2.73522.275 523.5 B2 180-185 2.5 510.275 511.2 B3 195-200 3.03 536.291 537.3B4 123 2.43 518.3 519.7 B5 205 2.47 504.285 505.4 B6 260-265 2.88514.249 515.3 B7 175-180 2.27 490.269 491.3 B8 240-245 2.38 460.259461.5 B9 165-170 2.51 474.274 475.5 B10 228-230 2.13 546.319 546.2 B11168-171 2.37 560.335 560.5 B12 181-182 2.53 588.366 588.5 B13 210-2152.84 538.253 539.5 B14 220-222 3.22 494.63 495.3 B16 160-165 3.02 546.65547.4 B17 225-230 3.04 502.59 503.3 B18 222-223 2.83 484.6 485.3 C1160-165 2.84 523.259 524.8 C3 165-170 3.26 497.244 498.5 C3 oil 2.49522.275 523.6 C4 175-180 2.91 483.228 484.1 C5 165-170 2.49 536.291537.2 C6 176-178 2.85 465.55 466.3 C7 195-200 2.69 449.243 450.4 D1135-140 2.52 473.19 474.6 D′1 120-130 2.68 551.167 552.7 H1 219-220 7.03406.192 407.3 H2 194-195 7.43 420.207 421.2 H4 96 8.44 405.196 406.3 H595 2.79 405.196 406.5 I1 180 2.86 423.207 424.2 I2 170 2.25 423.207424.5 I3 165 6.5 423.207 424.4 I4 186 2.64 409.191 410.2 I5 145 2.77423.207 424.2 I6 153 2.73 411.207 412 I7 235-240 5.83 425.186 426.3 I9205-210 6.07 481.212 481.9 I10 160-165 5.76 479.233 480 I11 185-190 7.07457.191 458.4 I12 235-240 7.08 457.191 458.2 I13 140-145 5.29 437.186438.4 I14 180-185 6.73 459.188 460.5 I16 218 5.21 425.186 426 I17 1956.48 437.223 438.5 I19 205 6.47 423.207 424.5 I20 275-280 7.85 463.238464.5 I21 165-170 7.45 435.207 436.6 I22 155-160 5.83 437.186 438.3 I23245-249 7.46 443.176 444.7 I24 242-243 7.82 485.223 486.5 I27 160-1656.43 441.198 442.4 I28 174-175 6.7 406.49 407.5 I29 179-181 5.06 424.202425.3 I30 215-216 5.33 438.218 439.3 I31 238-240 6.91 463.163 464.1 I32274-276 2 446.243 447.3 I33 165-170 6.02 481.212 482.2 I34 205-210 6.56459.188 460.5 J1 173 6.63 441.198 442.4 J2 195-200 2.88 423.207 424.1 K1165-170 8.21 458.175 459.5 K2 210 2.9 424.191 425.3 K3 150-155 8.17458.175 459.5 K4 133-134 8.16 438.207 439.5 K5 148 7.24 424.191 425.5 D2oil 2.69 499.205 500.7 D3 195-200 7.62 487.205 488.2 D4 210-212 7.25491.18 492.2 E1 210-215 3.3 503.244 504.1 E2 195-200 2.47 514.249 515.2E3 155-160 2.41 503.244 504.1 E4 175-180 3.41 465.254 466.3 E5 170-1753.31 463.238 464.2 E6 245-250 3.07 462.218 463.1 E7 175-180 3.12 481.249482.3 E8 225-230 2.97 477.58 478.5 E9 255-260 2.33 544.316 545.5 E10225-230 7.85 463.238 464.2 E11 145 2.91 463.238 464.2 E12 — 2.74 463.238464.5 E13 245-250 3.23 497.199 498.4 E14 265-270 2.52 445.248 446.4 E15260-265 2.62 431.232 432.4 E16 223 2.64 459.263 460.5 E17 282-284 2.17487.282 487.6 E18 299-300 2.58 500.29 501.7 E19 261-262 2.77 528.321529.6 E20 268-270 3.24 447.263 448.2 E21 243-244 3.21 445.56 446.2 E22196-198 3.12 485.254 486.3 E23 232-234 2.29 496.61 497.5 E24 225-2302.86 495.228 496.5 E25 155-160 2.65 494.244 495.4 E26 190-195 3.01477.218 478.1 E27 215-220 2.75 508.26 509.2 E28 180-185 2.92 522.275523.4 E29 204-205 6.04 490.269 491.3 E30 277-279 2.4 452.199 453.3 F1150-151 2.14 425.222 426.3 F2 oil 2.37 439.237 440.3 K6 235-240 8.44486.207 487.5 K8 105-110 8.08 472.191 473.6 L1 196 3.13 463.238 464.3 L2178 2.27 494.281 495.6 L3 188 3.32 465.254 466.3 L4 174 2.22 508.26509.4 L5 177 2.7 467.233 468.3 L6 180 6.04 439.202 440.3 L7 168 3.32503.233 504.2 L8 156 3.49 519.21 520.5 L9 140 6.27 492.265 493.3 L10 1943 501.185 502.4 L11 165-170 7.5 529.212 530.3 M1 205-210 8.25 450.207451.5 M3 198-200 6.55 451.202 452.2 M4 173-175 6.85 465.218 466.3 M6152-153 8.42 500.161 503.3 M7 — 7.95 450.2 451 M8 268-269 6.8 485.186486.4 M10 243-245 7.07 499.202 500.6 M11 225-230 8.06 484.191 485.2 M12197-199 6.41 482.183 483.2 M13 oil 7.47 464.54 465.2 N1 140-145 7.08449.223 450.5 O1 — 8.048 464.222 465.3 P1 120 3.22 487.205 488.2 P2 2292.29 459.174 460.4 P3 116 2.94 473.19 474.2 Q1 125-130 7.89 452.222453.3 R1  95-100 7.04 451.238 452.4 S1 162-163 2.43 369.162 370.4 T1210-215 2.37 464.234 465.5 U1 185-190 2.19 523.271 524.8 V1 215-220 5.66424.202 425.1 F19 160° C. 2.22 519.2 520.3 F20 150° C. 2.4 519.2 520.3F21 172° C. 2.24 513.2 514.3 F22 — 2.4 535.2 536.2 F23 170° C. 2.19535.2 536.4 F24 114.73° C. 2.28 501.2 502.2 F25 183.69° C. 2.26 501.2502.3 M14 165° C. 1.93 485.2 486.4 M15 135.05° C. 2.4 484.2 485.1 M16187° C. 2.4 525.2 526.3 M17 145° C. 2.3 498.2 499.4 M18 — 2.44 498.2499.2 M19 150° C. 2.46 476.2 477.3 O2 — 2.38 464.2 465.4 W1 240.93° C.2.3 450.2 451.1 W2 240.87° C. 2.32 484.2 485.2 X1 178.37° C. 2.23 479.2480.3 Y1 215.31° C. 2.66 463.2 464.3 Z1 238.19° C. 2.37 474.2 475.1 Z2168.55° C. 2.3 478.2 479.3 Z3 131.54° C. 3.33 431.2 432.2 Z4 202.06° C.3.11 465.2 466.5 Z5 — 2.62 504.3 505.3 F31 257.89 2.45 527.23 528.3 F32— 2.47 527.2 528.3 F33 — 2.19 475.2 476.2 F34 198.45 2.48 508.2 509.2F35 268.78 2.18 502.2 503.1 F36 274.48 2.4 474.2 475.3 F37 — 2.83 506.3507.3 F38 — 2.28 490.2 491.2 F39 230.94 2.44 504.2 505.2 F40 213.87 2.26464.2 465.1 M19 2.46 476.2 477.3 M20 228.12 2.19 476.2 477.6 M21 128.892.29 462.2 463.2 M22 214.14 2.45 476.2 477.2 M23 231.54 2.49 476.2 477.1M24 213.66 2.09 466.2 467.1 M27 202.04 2.4 496.2 497.2 M28 — 2.29 462.2463.2 O3 — 2.62 490.2 491.2 W2 — 2.26 490.2 491.2 W3 207.63 2.23 490.2491.3 W4 — 2.52 507.3 508.4 W5 — 2.52 507.3 508.3 W6 214.84 2.41 493.2494.2 W7 205.80 2.41 493.2 494.2 W8 232.32 2.25 502.2 503.2 W9 142.162.41 516.2 517.2 W10 239.85 2.39 516.2 517.2 W11 277.45 2.48 505.2 506.3W12 252.19 2.63 531.3 532.3 F41 197.2 2.5 529.249 530.3 F42 189.39 2.25480.217 481.1 F43 177.53 2.32 507.174 508.1 F44 — 2.21 464.186 465.2 F45— 2.2 475.202 476.1 F46 282.17 2.31 478.202 479.2 O10 333.75 2.49490.238 491.3 O11 249.19 2.52 490.238 491.2 O12 204.71 2.19 465.218466.2 O13 — 2.46 466.238 467.2 O14 — 2.46 466.238 467.2 O15 — 2.53498.207 499.3 F47 — 2.97 518.269 519.3 F48 204.93 2.28 480.217 481.3 F49218.14 2.31 518.196 519.2 F50 — 2.45 539.233 540.3 F51 261.88 2.42504.217 505.2 F52 — 2.8 504.254 505.3 F53 175.52 2.33 518.196 519.3 F54256.44 2.49 512.186 513.3 F55 — 2.42 541.158 542.3 F56 — 2.51 558.158559.3 F57 — 2.42 513.218 514.4 F58 — 2.55 555.174 556.4 F59 — 2.28538.213 539.3 F60 270.54 2.41 541.158 542.2 F61 — 2.26 501.181 502.1 F62— 2.24 520.212 521.2 F63 255.4 2.43 541.158 542.2 F64 195.6 2.3 480.217481.2 F65 186.2 2.29 480.217 481.2 F66 256.54 2.45 518.142 519.2 F67 —2.47 544.158 545.2 F68 203.36 2.5 567.174 568.3 F69 176.26 2.84 504.254505.3 I35 242 6.32 446.187 446.9 I36 165-170 6.92 460.202 461.3 I37250-255 5.51 447.182 448.5 I38 205-210 7.21 496.202 497.7 K9 155-1607.46 447.171 448.4 M29 176 2.52 478.238 479.2 M30 163 2.17 502.213 503.2M31 — 2.2 450.207 451.2 M32 — 2.3 480.217 481.2 M33 — 2.22 492.217 493.2M34 238.95 2.37 480.217 481.2 M35 206.72 2.45 488.222 489.3 M36 199.022.53 510.207 511.3 M37 200.99 2.33 477.218 478.2 M38 195.53 2.29 438.207439.2 M39 230.29 2.47 488.222 489.2 O16 333.46 2.58 464.222 465.2 O17219.7 2.3 506.233 507.2 O18 — 2.39 500.203 501.2 O19 — 2.34 487.202488.2 O20 252.97 2.48 516.163 517.2 O21 207.61 2.65 530.179 531.3 O22228.98 2.5 504.163 505.2 O23 239.3 2.43 526.219 527.4 O24 — 2.68 492.254493.5 O5 222.18 2.52 510.207 511.3 O6 — 2.38 476.222 477.2 O7 245.752.35 476.222 477.2 O8 — 2.58 524.222 525.3 O9 — 2.54 490.238 491.3 W13215.1 2.43 518.244 519.3 W14 199.65 2.69 521.28 522.3 W15 189.89 2.56519.265 520.3 W16 — 2.38 479.233 480.2 W17 172.28 2.64 507.265 508.3 W18276.58 2.35 523.26 524.3 W19 — 2.3 467.233 468.2 W20 132 2.43 530.244531.3 W21 — 3.22 533.255 534.3 W22 — 2.62 507.265 508.3 W23 182.69 2.58507.265 508.3 W24 — 1.59 478.177 479.1 W25 — 2.46 504.228 505.3 W26238.58 2.48 550.213 551.3 W27 144.43 2.36 524.197 525.2 W28 218.99 2.33527.233 528.5 W29 — 2.18 490.213 491.2 W30 — 2.63 519.265 520.3 W31 —2.41 519.265 520.6 W32 268.79 2.18 491.208 492.2 W33 257.75 2.41 536.197537.2 W34 162.08 2.71 553.249 554.4 W35 145.75 2.42 524.174 525.2 W36223.2 2.23 532.223 533.2 W37 231.1 2.52 545.19 546.2 M40 104.88 2.18451.202 452.1 M41 225-230 6.67 474.182 475.4 M42 240-245 8.05 487.202488.3 M43 255-260 4.42 473.186 474.1 M44 127.94 2.24 473.186 474.1 M45227.94 2.26 473.186 474.1 M46 265.43 2.42 502.147 503.1 M47 225.94 2.52516.163 517.2 M48 255.50 2.37 490.147 491.1 M49 262.19 2.38 490.147491.2 M50 184.15 2.61 490.238 491.2 M51 227.14 2.71 488.222 489.2 W38214.0 2.54 539.233 540.3 W39 265.13 2.43 556.169 557.2 W40 168.11 2.33530.154 531.1 W41 257.83 2.38 542.154 543.2 W43 252.56 2.31 533.19 534.5W44 — 2.69 559.205 560.3 W46 223.0 2.58 555.246 556.3 W47 — 2.73 541.249542.3 W48 227.9 2.69 547.205 548.3 W49 179.2 2.64 507.265 508.3 W50110.2 2.65 507.265 508.3 W51 203.3 2.45 506.2 505.2

Optical Rotation

The optical rotation was measured using a polarimeter with light at thewavelength of the D-line of sodium (589 nm) at a temperature of 20° C.in DMF as solvent.

Co. No. [α]_(D) ²⁰ c (w/v %) A26 −17.19  0.3664 A27  −9.53 0.3673 E10−14.88  0.3764 F15 −12.89  0.38 H4 −20.05  0.3891 I1 −16.5   0.3818 I4 −3.36 0.3873 I19 −6.1  0.3773 K5 −18.75  0.32 M3  −5.89 0.3736 M4−22.59  0.3718 M7 −18.31  0.344 M12 −12.51  0.3436 S1 −12.77  0.3836 F19−12.63  0.246 F20 −14.4   0.250 F21 −15.03  0.273 F23 −22.46  0.285 F24 −6.72 0.238 F25 −12.26  0.310 M14 −25.85  0.182 M15 −27.04  0.233 M16−30.54  0.203 M19 −22.73  0.220 O2 +150.87   0.269 W1 −14    0.250 W2−20    0.280 X1 −15.83  0.278 Y1 −17.45  0.2636 Z1  −4.56 0.241 Z2−12.63  0.246 Z3  −7.51 0.226 Z5 −17.19  0.320 F31 −12.96° 0.27 F32−13.58° 0.265 F33 −27.62° 0.21 F34 −11.2°  0.25 F36  −7.97° 0.251 F37−22.96° 0.27 F39 −13.33° 0.3 F40 −17.54° 0.217 M19 −29.1°  0.244 M20−11.42° 0.289 M21 −21.2°  0.25 M22  −9.86° 0.233 M23 −10.91° 0.183 M24−22.86° 0.175 M27 −25.83° 0.24 O3 −64.22° 0.237 W2 −12.64° 0.261 W3 −7.49° 0.427 W4 −102.73°  0.22 W5 +47.22° 0.324 W6 −27.59° 0.261 W7+28.62° 0.29 W8 −20.17° 0.238 W9 −20.37° 0.27 W10 −78.26° 0.23 W11−20.87° 0.115 W12 −15.38° 0.26 F41 −24.17° 0.24 F43 −11.79° 0.28 F44−12.13° 0.231 F45 −10°   0.3 F46 −6.4° 0.25 F47 −17.67° 0.3 F48 −23.56°0.225 F49 +28.57° 0.28 F51  −8.96° 0.201 F53 −5.4° 0.278 F54 −19.69°0.325 F62  −8.75° 0.32 F63 −29.31° 0.29 F64 −10.88° 0.239 F65 −30.84°0.227 F66 −27.22° 0.36 M29 −13.48° 0.23 M30 −11.9°  0.21 M31 −19.94°0.261 M32 −17.07° 0.217 M33  −6.09° 0.23 M34 −10.14° 0.178 M36 −24°  0.208 O19 +134.78°  0.276 M44 −36.73° 0.226 M46 −32.85° 0.274 M49−31.86° 0.242 O10 +169.34°  0.168 O11 +170.26°  0.237 O15 +157.19° 0.278 O16 −22.5°  0.28 O17 +166.15°  0.26 W41 −33.87° 0.31 W43 −76.15°0.26 W44 +16.21° 0.29 W46 +27.56° 0.254 W48 −28.57° 0.259 W49 −65.6° 0.25 W50 +31.29° 0.278 W51 +30.67° 0.225

E. Pharmacological Examples E.1 Antiviral Activity

Black 384-well clear-bottom microtiter plates (Coming, Amsterdam, TheNetherlands) were filled via acoustic drop ejection using the echoliquid handler (Labcyte, Sunnyvale, Calif.). 200 nL of compound stocksolutions (100% DMSO) were transferred to the assay plates. 9 serial4-fold dilutions of compound were made, creating per quadrant the samecompound concentration. The assay was initiated by adding 10 μL ofculture medium to each well (RPMI medium without phenol red, 10%FBS-heat inactivated, 0.04% gentamycin (50 mg/mL). All addition stepsare done by using a multidrop dispenser (Thermo Scientific, Erembodegem,Belgium). Next, rgRSV224 virus (MOI=1) diluted in culture medium wasadded to the plates. rgRSV224 virus is an engineered virus that includesan additional GFP gene (Hallak LK, Spillmann D, Collins PL, Peeples Me.Glycosaminoglycan sulfation requirements for respiratory syncytial virusinfection; Journal of virology (2000), 74(22), 10508-13) and wasin-licensed from the NIH (Bethesda, Md., USA). Finally, 20 μL of a HeLacell suspension (3,000 cells/well) were plated. Medium, virus- andmock-infected controls were included in each test. The wells contain0.05% DMSO per volume. Cells were incubated at 37° C. in a 5% CO2atmosphere. Three days post-virus exposure, viral replication wasquantified by measuring GFP expression in the cells by an in housedeveloped MSM laser microscope (Tibotec, Beerse, Belgium). The EC50 wasdefined as the 50% inhibitory concentration for GFP expression. Inparallel, compounds were incubated for three days in a set of white384-well microtiter plates (Corning) and the cytotoxicity of compoundsin HeLa cells was determined by measuring the ATP content of the cellsusing the ATPlite kit (Perkin Elmer, Zaventem, Belgium) according to themanufacturer's instructions. The CC50 was defined as the 50%concentration for cytotoxicity.

TABLE antiviral data Co. No. RSV HELA pEC50 TOX HELA pCC50 A1 5.30 <4.30A2 5.52 <4.60 A3 5.45 4.40 A4 5.99 4.34 A5 5.32 4.48 A6 6.14 4.24 A76.23 <4.60 A8 6.19 <4.60 A9 6.27 <4.60 A10 5.68 <4.60 A11 6.19 <4.60 A126.06 <4.60 A13 6.48 <4.60 A14 6.40 <4.60 A15 6.47 <4.60 A16 5.57 4.45A17 5.82 4.39 A18 6.45 <4.00 A19 5.34 4.42 A20 5.20 <4.60 A21 6.05 <4.00A22 6.22 <4.60 A24 6.52 <4.60 A25 6.26 <4.00 A26 6.71 <4.60 A27 6.06<4.60 A28 6.10 <4.60 A29 6.81 <4.60 A30 6.08 <4.00 A31 6.20 <4.60 A325.97 <4.60 B1 6.89 <4.00 B2 6.39 <4.00 B3 7.10 <4.60 B4 6.59 4.26 B56.78 <4.00 B6 6.13 <4.00 B7 6.20 <4.00 F3 6.08 <4.00 F4 6.14 <4.60 F56.51 <4.60 F6 6.45 <4.60 F7 5.68 <4.60 F8 5.63 <4.60 F9 6.18 <4.60 F106.16 <4.60 F11 5.87 <4.60 F12 5.86 <4.60 F13 6.25 <4.60 F14 6.74 <4.60F15 6.92 <4.60 F16 6.84 <4.60 F17 6.19 <4.60 F18 6.70 <4.60 G1 6.55<4.60 H1 6.25 <4.60 H2 6.04 <4.60 H4 6.18 <4.60 H5 6.09 <4.60 I1 7.27<4.60 I2 7.25 <4.30 I3 5.65 <4.60 I4 6.51 <4.60 I5 5.23 <4.60 I6 6.38<4.60 I7 5.99 <4.60 I9 5.87 <5.00 I10 6.64 <4.60 I11 6.55 <4.60 I12 7.52<4.60 I13 6.12 <4.60 I14 6.47 <4.60 I16 5.61 <4.60 I17 5.58 <4.60 I196.60 <4.60 I20 5.10 <4.60 B8 6.62 4.77 B9 6.30 <4.00 B10 6.50 <4.00 B116.55 <4.00 B12 6.72 <4.00 B13 6.40 <4.60 B14 6.36 <4.60 B16 6.23 <4.60B17 6.39 <4.60 B18 5.94 <4.60 C1 6.46 <4.00 C3 6.78 <4.60 C3 6.55 4.89C4 6.96 <4.60 C5 6.75 4.86 C6 6.27 <4.60 C7 5.86 <4.00 D1 6.54 4.29 D′16.68 <4.00 D2 6.22 <4.30 D3 6.84 <4.60 D4 6.31 <4.60 E1 6.21 <4.60 E27.03 <4.60 E3 6.88 5.19 E4 6.74 <4.60 E5 6.86 <4.60 E6 6.78 <4.60 E76.93 <4.60 E8 6.33 <4.60 E9 6.77 <4.60 E10 7.04 <4.60 E11 6.20 <4.60 E126.35 4.22 E13 5.83 <4.60 E14 6.51 <4.30 E15 6.08 <4.017 E16 5.88 <5.00E17 6.29 <4.30 E18 5.90 <4.60 I21 6.09 <4.60 I22 6.16 <4.60 I23 5.26<4.60 I24 6.10 4.76 I27 6.60 <4.60 I28 5.75 <4.60 I29 6.53 <4.60 I306.62 <4.60 I31 6.85 <4.60 I32 6.35 <4.60 I33 7.06 <4.60 I34 6.64 <4.60J1 6.83 <4.60 J2 6.58 <4.60 K1 6.80 <4.60 K2 6.25 <4.60 K3 5.96 <4.60 K46.56 <4.60 K5 6.51 <4.60 K6 5.62 <4.60 K8 6.36 <4.60 L1 6.89 <4.60 L26.26 <4.60 L3 6.62 <4.60 L4 6.63 <4.60 L5 6.80 <4.60 L6 6.83 4.69 L76.62 <4.60 L8 6.49 <4.60 L9 6.43 <4.60 L10 5.57 <4.60 L11 6.20 <4.60 M16.76 <4.60 M3 6.60 <4.60 M4 6.80 <4.60 M6 6.84 <4.60 M7 7.00 <4.60 M87.31 <4.60 M10 7.32 4.70 M11 7.42 <4.60 E19 6.27 <4.00 E20 6.16 <4.60E21 6.22 <4.60 E22 5.77 4.66 E23 6.19 <4.60 E24 6.55 <4.60 E25 7.21<4.60 E26 6.39 <4.60 E27 6.93 <4.60 E28 6.93 <4.60 E29 6.34 <4.60 E305.74 <4.60 F1 6.06 4.42 F2 5.53 4.41 M12 5.39 <4.60 M13 6.65 <4.60 N16.89 <4.60 O1 6.91 <4.60 P1 5.55 <4.60 P2 6.19 <4.60 P3 6.16 <4.60 Q16.27 <4.60 R1 6.60 <4.60 S1 6.08 <4.00 T1 6.26 <4.00 U1 6.28 <4.00 V15.72 <4.60 F31 7.31 4.49 F32 7.55 4.49 F33 7.04 4.18 F34 7.46 4.17 F356.79 <4 F36 7.33 <4 F37 6.74 4.42 F38 7.29 4.44 F39 7.41 4.35 F40 6.884.28 M19 7.52 4.41 M20 7.49 4.44 M21 7.16 4.34 M22 7.34 4.05 M23 7.35 <4M24 6.42 <4 M27 7.93 — M28 7.03 4.75 O3 7.06 4.22 W2 7.21 <4.60 W3 6.974.22 W4 6.98 4.05 W5 7.05 4.02 W6 7.09 4.16 W7 7.32 4.15 W8 7.11 4.26 W97.33 4.29 W10 7.51 4.28 W11 6.63 4.23 W12 6.69 4.20 F19 7.01 4.44 F207.07 4.30 F21 7.28 4.37 F22 7.45 5.16 M19 7.72 4.49 O2 7.23 <4.60 W17.19 <4.60 W2 7.91 4.31 F23 7.39 <4.60 F24 7.16 4.90 F25 7.36 4.87 M147.62 4.80 M15 7.82 <4.69 M16 7.88 4.78 M17 7.20 4.76 M18 7.11 <4.60 X17.03 <4.60 Y1 7.19 <4.60 Z1 7.22 <4.60 Z2 7.26 <4.60 Z3 7.02 <4.60 Z47.11 <4.60 Z5 7.19 4.36 F41 7.44 4.65 F42 7.16 <4 F43 7.21 4.37 F44 6.404.25 F45 7.36 4.04 F46 7.31 <4 F47 6.61 4.33 F48 6.36 <4 F49 7.58 4.24F50 6.49 4.22 F51 7.56 4.24 F52 6.81 4.22 F53 7.44 4.22 F54 8.59 4.75F55 6.92 <4 F56 6.81 <4 F57 6.69 4.52 F58 6.77 4.58 F59 6.72 <4.60 F607.34 <4.60 F61 7.34 <4 F62 7.24 <4.60 F63 7.34 4.35 F64 7.12 <4 F65 6.85<4 F66 8.15 4.81 F67 7.40 4.17 F68 7.36 4.29 F69 6.71 <4.6 M49 8.00 4.38M50 6.72 4.33 M51 6.79 4.18 O5 7.96 4.26 O6 6.83 4.01 O7 7.40 4.34 O87.93 4.31 O9 6.96 4.05 O10 7.54 4.34 O11 7.52 4.32 O12 6.76 <4 O13 6.854.34 O14 6.66 4.18 O15 7.91 4.32 O16 6.77 <4 O17 7.29 4.11 O18 6.72 4.27O19 7.51 4.04 O20 8.09 4.28 O21 7.96 4.26 O22 8.16 4.32 W13 7.45 4.38W14 7.53 4.29 W15 7.29 4.24 W16 6.57 <4 W17 7.66 4.23 W18 7.09 <4 W196.58 <4 W20 6.45 4.20 I35 7.36 <4.60 I36 6.58 <4.60 I37 6.24 <4.60 I385.75 <4.60 K9 6.28 <4.60 M29 7.41 4.17 M30 7.39 4.55 M31 6.13 <4 M326.75 4.18 M33 6.99 <4 M34 7.04 <4 M35 6.70 4.37 M36 7.99 4.26 M37 7.10<4 M38 6.65 <4 M39 6.19 <4 M40 6.37 <4 M41 6.10 <4.60 M42 6.72 <4.60 M437.32 <4.60 M44 7.74 <4.60 M45 7.54 <4 M46 8.30 4.17 M47 7.87 4.07 M487.89 <4.60 W21 5.99 4.66 W22 7.34 4.06 W23 7.12 4.10 W25 7.03 4.18 W267.63 <4 W27 7.40 4.33 W28 8.37 4.29 W29 6.44 <4 W30 7.76 4.30 W31 7.904.31 W32 6.66 <4 W33 7.79 4.24 W34 7.95 4.36 W35 6.72 <4.6 W36 6.82<4.60 W37 8.25 4.34 W38 8.24 4.33 W39 7.55 4.26 W40 7.66 4.44 W41 7.88<4.6 W43 8.56 4.31 W44 8.06 4.31 W49 7.36 4.27 W50 7.35 4.13 W51 7.414.16

F. Prophetic Composition Examples

“Active ingredient” as used throughout these examples relates to a finalcompound of Formula (I), the pharmaceutically acceptable salts thereof,the solvates and the stereochemically isomeric forms and the tautomersthereof.

Typical examples of recipes for the formulation of the invention are asfollows:

F.1. Tablets

Active ingredient 5 to 50 mg Di calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate  5 mg Potato starch ad 200 mg

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

F.2. Suspension

An aqueous suspension is prepared for oral administration so that each 1milliliter contains 1 to 5 mg of one of the active compounds, 50 mg ofsodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg ofsorbitol and water ad 1 ml.

F.3. Injectable

A parenteral composition is prepared by stirring 1.5% by weight ofactive ingredient of the invention in 10% by volume propylene glycol inwater.

F.4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g  Water ad 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

Reasonable variations are not to be regarded as a departure from thescope of the invention. It will be obvious that the thus describedinvention may be varied in many ways by those skilled in the art.

1. A compound of formula (I), including any stereochemically isomericform thereof, wherein

including any stereochemically isomeric form thereof, wherein X is N orCR⁶ wherein R⁶ is hydrogen, halo or C₁₋₄alkyl; R¹ is CH₃ or CH₂CH₃, andR^(1′) is hydrogen; or R¹ and R^(1′) are taken together with the carbonatom to which they are attached to form cyclopropyl; and R² is C₃₋₆alkyland R³ is C₁₋₄alkyl; or the

moiety is a radical of formula:

wherein R¹ is CH₃ or CH₂CH₃, and R^(1′) is hydrogen; or is absent inradical (a-6); or R¹ and R^(1′) are taken together with the carbon atomto which they are attached to form cyclopropyl; and radical (a-1) to(a-30) are optionally substituted with one or two substituents eachindependently selected from C₁₋₂alkyl and halo; R⁴ is C₁₋₆alkyl;C₃₋₆alkenyl, polyhaloC₁₋₄alkyl; C₁₋₄alkyl substituted with oneC₃₋₆cycloalkyl; aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl;oxetanyl optionally substituted with C₁₋₄alkyl; Heteroaryl¹;C₃₋₆cycloalkyl; C₃₋₆cycloalkyl substituted with one or two substituentseach individually selected from hydroxy, halo, cyano, C₁₋₄alkyl,C₁₋₄alkyloxy, polyhaloC₁₋₄alkyl, and polyhaloC₁₋₄alkyloxy; or NR⁷R⁸wherein R⁷ is selected from hydrogen and C₁₋₄alkyl; R⁸ is C₁₋₄alkyl orC₃₋₆cycloalkyl; or R⁷ and R⁸ are taken together with the nitrogen towhich they are attached to form azetidinyl, pyrrolidinyl or piperidinyl;R⁵ is C₃₋₆cycloalkyl; Heteroaryl; Bicycle; naphthyl substituted with 1,2 or 3 substituents each independently selected from halo andhydroxycarbonyl; phenyl substituted with 1, 2 or 3 substituents eachindependently selected from hydroxy; halo; C₁₋₆alkyl; C₁₋₆alkylsubstituted with one, two or three substituents each independentlyselected from halo, hydroxy, hydroxycarbonyl, aminocarbonyl,Heterocycle, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl substituted with one or twosubstituents each independently selected from C₁₋₄alkyl, halo,hydroxycarbonyl, and C₁₋₄alkyl substituted with hydroxycarbonyl;C₃₋₆alkenyl; C₃₋₆alkenyl substituted with one or two substituentsselected from C₁₋₆alkyl, hydroxy, hydroxycarbonyl and aminocarbonyl;C₃₋₆alkynyl; C₃₋₆alkynyl substituted with one hydroxycarbonyl;C₃₋₆cycloalkyl; C₃₋₆cycloalkyl substituted with one, two or threesubstituents each independently selected from C₁₋₄alkyl, halo,hydroxycarbonyl, and C₁₋₄alkyl substituted with hydroxycarbonyl;C₃₋₆cycloalkenyl; C₃₋₆cycloalkenyl substituted with one hydroxycarbonyl;C₁₋₆alkyloxy optionally substituted with hydroxycarbonyl;polyhaloC₁₋₄alkyl; polyhaloC₁₋₄alkyloxy; cyano; nitro; B(OH)₂;hydroxycarbonyl; CO—NHOH; CO—NR⁹R¹⁰; CO—NH—NR⁹R¹⁰; NR⁹R¹⁰; NH—CO—R¹¹;NH—CO—O—R¹¹; NH—CO—NH—R¹¹; NH—CS—NH—R11; NH—C═(N—CN)—NH—R¹¹;aminosulfonyl; mono- or di(C₁₋₄alkyl)aminosulfonyl; Heterocycle; andspiro[3.3]heptanyl optionally substituted with hydroxycarbonyl; whereinR⁹ and R¹⁰ are each independently selected from hydrogen; C₁₋₆alkyl;SO₂—R¹²; and C₁₋₆alkyl substituted with one or two substituents eachindependently selected from hydroxy, hydroxycarbonyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl substituted with hydroxycarbonyl, C₁₋₄alkylcarbonylamino,mono- or di(C₁₋₄alkyl)amino, and Heterocycle; R¹¹ is C₁₋₆alkyl;C₃₋₆alkenyl; C₃₋₆cycloalkyl; Aryl; Heterocycle; or C₁₋₆alkyl substitutedwith one substituent selected from C₃₋₆cycloalkyl, hydroxy, cyano,hydroxycarbonyl, aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl,C₁₋₄alkylcarbonylamino, and Heterocycle; R¹² is C₁₋₄alkyl,C₃₋₆cycloalkyl, or C₁₋₄alkyl substituted with one C₃₋₆cycloalkyl,Heteroaryl is thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl,1-benzopyrazolyl, 2,3-dihydro-1H-indolyl, 2-oxo-2,3-dihydro-1H-indolyl,quinolinyl, 2-oxo-quinolinyl, benzimidazolyl, cinnolinyl, or2H-chromenyl, wherein each Heteroaryl is optionally substituted with oneor two substituents each independently selected from C₁₋₄alkyl, halo,amino, aminocarbonyl, and NH—CO—C₃₋₆cycloalkyl; Heteroaryl¹ isimidazolyl or pyrazolyl; wherein each Heteroaryl¹ is optionallysubstituted with one or two substituents each independently selectedfrom C₁₋₄alkyl, halo and hydroxycarbonyl; Heterocycle is azetidinyl,tetrahydrofuranyl, pyrrolidinyl, furanyl, thienyl, imidazolyl,pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl,2,5-dihydro-1H-pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl,2-oxo-azepanyl, 2,5-dioxopyrrolidinyl, or3-oxo-2,3-dihydro-1,2-oxazolyl; wherein each Heterocycle is optionallysubstituted with one or two substituents each independently selectedfrom C₁₋₄alkyl, C₃₋₆cycloalkyl, halo, hydroxyC₁₋₄alkyl, hydroxycarbonyl,and C₁₋₄alkyl substituted with hydroxycarbonyl; Aryl is phenylsubstituted with one or two substituents each independently selectedfrom hydrogen, halogen, C₁₋₄alkyl, C₁₋₄alkyloxy, and trifluoromethyl;Bicycle is 1,2,3,4-tetrahydronaphthalenyl, chromanyl or2,3-dihydrobenzofuranyl; wherein each Bicycle is optionally substitutedwith one or two substituents each independently selected from C₁₋₄alkyl,halo and hydroxycarbonyl; with the proviso that[7-ethyl-2-(3-thienyl)pyrazolo[1,5-a]pyrimidin-5-yl](2-methyl-1-piperidinyl)-methanoneand[7-ethyl-2-(2-pyridinyl)pyrazolo[1,5-a]pyrimidin-5-yl](2-methyl-1-piperidinyl)-methanoneare not included; or a pharmaceutically acceptable acid addition saltthereof.
 2. The compound as claimed in claim 1 wherein X is N or CR⁶wherein R⁶ is hydrogen or halo; R¹ is CH₃ or CH₂CH₃, and R^(1′) ishydrogen; or R¹ and R^(1′) are taken together with the carbon atom towhich they are attached to form cyclopropyl; and R² is C₃₋₆alkyl and R³is C₁₋₄alkyl; or the

moiety is a radical of formula:

wherein R¹ is CH₃ or CH₂CH₃, and R^(1′) is hydrogen; or R^(1′) is absentin radical (a-6); or R¹ and R^(1′) are taken together with the carbonatom to which they are attached to form cyclopropyl; and radical (a-1)to (a-15) are optionally substituted with one or two substituents eachindependently selected from C₁₋₂alkyl and halo; R⁴ is C₁₋₆alkyl;polyhaloC₁₋₄alkyl; C₃₋₆cycloalkyl; C₁₋₄alkyl substituted with oneC₃₋₆cycloalkyl; or NR⁷R⁸ wherein R⁷ is selected from hydrogen andC₁₋₄alkyl; R⁸ is C₁₋₄alkyl or C₃₋₆cycloalkyl; or R⁷ and R⁸ are takentogether with the nitrogen to which they are attached to formpyrrolidinyl or piperidinyl; R⁵ is C₃₋₆cycloalkyl; Heteroaryl; phenylsubstituted with 1, 2 or 3 substituents each independently selected fromhydroxy; halo; C₁₋₆alkyl; C₁₋₆alkyl substituted with one substituentselected from hydroxy, hydroxycarbonyl and aminocarbonyl; C₃₋₆alkenylsubstituted with one or two substituents selected from C₁₋₆alkyl,hydroxy, hydroxycarbonyl and aminocarbonyl; C₃₋₆cycloalkyl substitutedwith one hydroxycarbonyl; C₁₋₆alkyloxy; cyano; B(OH)₂; hydroxycarbonyl;CO—NHOH; CO—NR⁹R¹⁰; CO—NH—NR⁹R¹⁰; NR⁹R¹⁰; NH—CO—R¹¹; NH—CO—O—R¹¹;NH—CO—NH—R¹¹; NH—CS—NH—R¹¹; NH—C═(N—CN)—NH—R¹¹; aminosulfonyl; mono- ordi(C₁₋₄alkyl)aminosulfonyl; and Heterocycle; wherein R⁹ and R¹⁰ are eachindependently selected from hydrogen; C₁₋₆alkyl; SO₂—R¹²; and C₁₋₆alkylsubstituted with C₃₋₆cycloalkyl, mono- or di(C₁₋₄alkyl)amino, orHeterocycle; R¹¹ is C₁₋₆alkyl; C₃₋₆alkenyl; C₃₋₆cycloalkyl; Aryl;Heterocycle; or C₁₋₆alkyl substituted with one substituent selected fromC₃₋₆cycloalkyl, C₁₋₄alkyloxy, hydroxy, cyano, hydroxycarbonyl,aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl,C₁₋₄alkylcarbonylamino, and Heterocycle; R¹² is C₁₋₄alkyl, orC₃₋₆cycloalkyl; Heteroaryl is thienyl, pyridinyl, 1-benzopyrazolyl,2,3-dihydro-1H-indolyl, 2-oxo-2,3-dihydro-1H-indolyl, quinolinyl,2-oxo-quinolinyl, benzimidazolyl, cinnolinyl, or 2H-chromenyl, whereineach Heteroaryl is optionally substituted with one or two substituentseach independently selected from C₁₋₄alkyl, halo, aminocarbonyl, andNH—CO—C₃₋₆cycloalkyl; Heterocycle is azetidinyl, tetrahydrofuranyl,pyrrolidinyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl,pyridinyl, pyrimidinyl, pyrazinyl, 2-oxo-azepanyl,2,5-dioxopyrrolidinyl, or 3-oxo-2,3-dihydro-1,2-oxazolyl; wherein eachHeterocycle is optionally substituted with one or two substituents eachindependently selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, halo andhydroxycarbonyl; Aryl is phenyl substituted with one or two substituentseach independently selected from hydrogen and halogen; or apharmaceutically acceptable acid addition salt thereof.
 3. The compoundas claimed in claim 1 or claim 2 wherein X is N.
 4. The compound asclaimed in claim 3 wherein R¹ is CH₃ or CH₂CH₃, and R^(1′) is hydrogen,and R² is C₃₋₆alkyl and R³ is CH₃.
 5. The compound as claimed in claim 3wherein the

moiety is a radical of formula (a-1) to (a-15) wherein R¹ is CH₃ orCH₂CH₃, and R^(1′) is hydrogen; or R^(1′) is absent in radical (a-6); orR¹ and R^(1′) are taken together with the carbon atom to which they areattached to form cyclopropyl; and radical (a-1) to (a-15) are optionallysubstituted with one or two substituents each independently selectedfrom C₁₋₂alkyl and halo.
 6. The compound as claimed in claim 1 or claim2 wherein X is CR⁶ wherein R⁶ is hydrogen or halo.
 7. The compound asclaimed in claim 6 wherein R¹ is CH₃ or CH₂CH₃, and R^(1′) is hydrogen,and R² is C₃₋₆alkyl and R³ is CH₃.
 8. The compound as claimed in claim 6wherein the

moiety is a radical of formula (a-1) to (a-15) wherein R¹ is CH₃ orCH₂CH₃, and R^(1′) is hydrogen; or R^(1′) is absent in radical (a-6); orR¹ and R^(1′) are taken together with the carbon atom to which they areattached to form cyclopropyl; and radical (a-1) to (a-15) are optionallysubstituted with one or two substituents each independently selectedfrom C₁₋₂alkyl and halo.
 9. The compound as claimed in any one of claims1 to 8 wherein R⁵ is phenyl substituted with 1, 2 or 3 substituents eachindependently selected from halo; or C₁₋₆alkyl substituted with onesubstituent selected from hydroxy, hydroxycarbonyl and aminocarbonyl.10. The compound as claimed in any one of claims 1 to 8 wherein R⁵ isphenyl substituted with 1, 2 or 3 substituents each independentlyselected from halo; or C₃₋₆alkenyl substituted with one or twosubstituents selected from C₁₋₆alkyl, hydroxy, hydroxycarbonyl andaminocarbonyl.
 11. The compound according to claim 1, wherein thecompound is selected from

or a pharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically active amount of a compound as claimed in any of claims1 to
 11. 13. The pharmaceutical composition according to claim 12, whichfurther comprises another antiviral agent.
 14. The pharmaceuticalcomposition according to claim 13, wherein the other antiviral agent isa RSV inhibiting compound.
 15. A process for preparing a pharmaceuticalcomposition as claimed in any one of claims 12 to 14 wherein atherapeutically active amount of a compound as claimed in any of claims1 to 11 is intimately mixed with a pharmaceutically acceptable carrier.16. A compound as claimed in any of claims 1 to 11 for use as amedicine.
 17. A compound as claimed in any of claims 1 to 11, or apharmaceutical composition as claimed in claim 11, for use in thetreatment of a respiratory syncytial virus infection.
 18. A method oftreating a respiratory syncytial virus (RSV) infection comprisingadministering to a subject in need thereof an anti-virally effectiveamount of a compound of formula (I) as defined in any one of claims 1 to11.